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Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases

  • Zhouling Xie
    Zhouling Xie
    Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
    More by Zhouling Xie
  • Xiaoxiao Yang
    Xiaoxiao Yang
    Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
  • Yajun Duan
    Yajun Duan
    Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
    More by Yajun Duan
  • Jihong Han
    Jihong Han
    Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
    More by Jihong Han
  • , and 
  • Chenzhong Liao*
    Chenzhong Liao
    Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
    *E-mail: [email protected], [email protected]
Cite this: J. Med. Chem. 2021, 64, 3, 1283–1345
Publication Date (Web):January 22, 2021
https://doi.org/10.1021/acs.jmedchem.0c01511
Copyright © 2021 American Chemical Society
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Abstract

Great successes have been achieved in developing small-molecule kinase inhibitors as anticancer therapeutic agents. However, kinase deregulation plays essential roles not only in cancer but also in almost all major disease areas. Accumulating evidence has revealed that kinases are promising drug targets for different diseases, including cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system disorders, viral infections, and malaria. Indeed, the first small-molecule kinase inhibitor for treatment of a nononcologic disease was approved in 2011 by the U.S. FDA. To date, 10 such inhibitors have been approved, and more are in clinical trials for applications other than cancer. This Perspective discusses a number of kinases and their small-molecule inhibitors for the treatment of diseases in nononcologic therapeutic fields. The opportunities and challenges in developing such inhibitors are also highlighted.

1. Introduction

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As a large and varied multigene family of enzymes, kinases catalyze the transfer of the γ-phosphate group from the high-energy ATP molecule to specific substrates. Referred to as phosphorylation, this process produces a phosphorylated product and ADP. On the basis of the substrates they phosphorylate, kinases are classified into protein kinases, lipid kinases, carbohydrate kinases, and other kinases. Generally, phosphate groups are added to serine, threonine, or tyrosine residues in proteins. The phosphorylation state of a molecule has a large impact on its activity, reactivity, and capacity to bind other molecules. Kinases are pivotal in cell signaling, metabolism, protein regulation, secretory processes, cellular transport, and many other cellular pathways, therefore, kinases are crucial in human physiology. To date, 518 different kinases have been identified in humans, and they phosphorylate up to one-third of the proteome.(1) Deregulation of kinase signaling has been confirmed to play indispensable roles in virtually all major disease areas, including oncological, immunological, inflammatory, degenerative, metabolic, cardiovascular, and infectious diseases, therefore, kinases have been intensively investigated for drug development in different disease fields.(2−4)
Kinase inhibitors can be classified according to their structure and size as monoclonal antibodies (mAbs) or small-molecule kinase inhibitors (SMKIs). Spectacular successes have been achieved in developing mAbs as anticancer therapeutic agents. For example, as early as 1998, the first mAb, trastuzumab, was approved by the U.S. Food and Drug Administration (FDA) for treatment of HER2 receptor-positive breast cancer. However, because of the inherent disadvantages of mAbs, such as production cost, stability, and immunogenicity,(5) low-molecular-weight SMKIs have become an active research field in the discovery of kinase inhibitors. Targeting the human kinome has produced fruitful SMKIs for medical use. As of December 31, 2020, 63 SMKIs have been approved by the U.S. FDA (Figure 1), and several SMKIs, including icotinib (in China in 2011), apatinib (in China in 2014), anlotinib (in China in 2018), pyrotinib (in China in 2018), fruquintinib (in China in 2018), peficitinib (in Japan in 2019), flumatinib (in China in 2019), tirabrutinib (in Japan in 2020), almonertinib (in China in 2020), delgocitinib (in Japan in 2020), and filgotinib (in Japan and European Community in 2020), have been approved outside of the USA. In addition, a large number of SMKIs are currently in clinical trials. An online updated database named Protein Kinase Inhibitor Database (PKIDB) compiles SMKIs that have been in phase 0 to 4 clinical trials. Annotations extracted from seven public resources are supplied.(6) This database provides a good tool to analyze the SMKIs that are currently on the market or under development.

Figure 1

Figure 1. SMKIs approved by the U.S. FDA. The INNs of drugs (compounds 110) with indications other than cancer are displayed in magenta ellipsoids, and their chemical structures are shown.

Kinase deregulation plays essential roles in virtually all major disease areas. Accumulating evidence has revealed that kinases are promising drug targets for different diseases, including cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system (CNS) disorders, viral infections, and malaria. In 2001, the U.S. FDA approved the first SMKI, imatinib, and before 2011, the U.S. FDA approved nine SMKIs; however, these SMKIs were exclusively approved for cancer therapy. With the exception of 2016, breakthroughs have been made in the approval of SMKIs from 2011 to 2020: a few or several SMKIs were approved each year. In 2011, an SMKI named ruxolitinib (1), a JAK1 and JAK2 inhibitor, was approved for treatment of myelofibrosis, an indication different from cancer. This was the first SMKI approved for treatment of a nononcologic disease, which has brought a surge of interest in the development of SMKIs for both cancer and nononcologic diseases.(7) Indeed, after the approval of ruxolitinib, a total of 10 SMKIs have been approved by the U.S. FDA for indications other than cancer: ruxolitinib in 2011, tofacitinib (2) in 2012, ibrutinib (3) in 2013, nintedanib (4) in 2014, baricitinib (5), netarsudil (6), and midostaurin (7) in 2017, fostamatinib (8) in 2018, and upadacitinib (9)(8) and fedratinib (10)(9) in 2019 (Figure 1). These are significant achievements in kinase drug discovery. Table 1 summarizes the information on these 10 drugs. Among them, ibrutinib was first approved in 2013 for cancer therapy and was repurposed in 2017 and further approved for treatment of chronic graft versus host disease (GVHD), a medical complication that may occur after an allogeneic transplant.
Table 1. SMKIs with Indications for Nononcologic Diseases Approved by the U.S. FDAa,b
drugtargetcompanyapproved yearindications for nononcologic diseasesindications for cancernononcologic diseases in clinical trialscancer in clinical trials
ruxolitinib (1)JAK1, JAK2Incyte Corp.2011myelofibrosis, PCV PP, AA, atopic dermatitis, vitiligo, GVHDdiffuse LBCL, PTCL, pancreatic cancer, AML, glioblastoma, breast cancer, etc.
tofacitinib (2)Pan-JAKPfizer2012RA, PA, UC, AS, AA vitiligo, atopic dermatitis, CD, dry eye syndromes, COVID-19, SLE 
ibrutinib (3)BTKPharmacyclics Inc.2017 (in 2013, it was approved for cancer first)chronic GVHDCLL, WM, MCL, marginal zone lymphomafood allergy, COVID-19diffuse LBCL, small lymphocytic leukemia, gastroesophageal cancer, glioblastoma, lung cancer, etc.
nintedanib (4)multi tyrosine kinasesBoehringer Ingelheim2014IPF, interstitial lung diseasesNSCLClung transplant recipientsbladder cancer, metastatic bowel cancer, liver cancer, brain tumor glioblastoma multiforme, ovarian cancer
baricitinib (5)JAK1, JAK2Incyte Corp., Eli Lilly2017RA AA, COVID-19, GVHD, juvenile idiopathic arthritis, lupus erythematosus, arteritis, atopic dermatitis, liver diseases, uveitis, primary biliary cholangitis, psoriasis, etc. 
netarsudil (6)ROCK1, ROCK2Aerie Pharmaceutical2017glaucoma, ocular hypertension Fuchs’ endothelial dystrophy, cataract, bullous keratopathy, corneal edema 
midostaurin (7)multitarget kinasesNovartis2017systemic mastocytosisAML, myelodysplastic syndromehepatic impairmentrectal cancer, leukemia
fostamatinib (8)SYKRigel Pharmaceutical2018chronic ITP renal transplant rejection, RA, warm antibody autoimmune hemolytic anemia, immune thrombocytopenic purpuraovarian cancer, hematological malignancies, T-cell lymphoma
upadacitinib (9)JAK1Abbvie2019RA atopic dermatitis, spondyloarthritis, juvenile idiopathic arthritis, AS, takayasu arteritis, UC, CD, SLE, giant cell arteritis, PA 
fedratinib (10)JAK2Celgene2019myelofibrosis thrombocythemia, myelodysplastic syndrome, chronic beryllium disease, beryllium sensitizationAML
a

Clinical information in this table was mainly obtained from the Web site of www.clinicaltrials.gov.

b

Abbreviations used in this table: AA, alopecia areata; AML, acute myeloid leukemia; AS, ankylosing spondylitis; CD, Crohn’s disease; CLL, chronic lymphocytic leukemia; COVID-19, coronavirus disease 2019; GVHD, graft versus host disease; IPF, idiopathic pulmonary fibrosis; ITP, immune thrombocytopenia; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; NSCLC, Nonsmall cell lung cancer; PA, psoriatic arthritis; PCV, polycythemia vera; PP, plaque psoriasis; PTCL, peripheral T-cell lymphoma; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; UC, ulcerative colitis; WM, Waldenström’s macroglobulinemia.

SMKIs may selectively target one kinase, two kinases, or several kinases. For example, nintedanib (4), an SMKI indicated for idiopathic pulmonary fibrosis (IPF) and chronic fibrosing (scarring) interstitial lung diseases, inhibits fibroblast growth factor receptor 1–3, platelet-derived growth factor receptor (PDGFR) α and β, vascular endothelial growth factor receptor (VEGFR) 1–3, and FMS-like tyrosine kinase 3 (FLT3). Among these four kinase types, the first three are related to IPF pathogenesis. By binding competitively to the ATP-binding pockets of these kinases, this drug blocks the intracellular signaling pathways implicated in IPF pathology. Midostaurin (7) also targets multiple kinases, including FLT3. In both situations, the successes of these two drugs cannot be credited to a single kinase.
In addition to SMKIs, a few macrolides derived from the natural compound rapamycin that target a kinase named mammalian target of rapamycin (mTOR) were licensed for treatment of a few nononcologic diseases. The molecular weights of these macrolides are more than 900 Da, and thus, they are not considered typical SMKIs. In this Perspective, mTOR will be highlighted as a successful kinase target for the development of drugs for treatment of nononcologic diseases.
Aside from the human kinome, targeting kinomes of other species is an effective way to discover medicines to cure infectious diseases. In this field, the most striking example is the discovery of SMKIs for treatment of human malaria. However, no SMKIs targeting kinases not present in humans have been approved. This Perspective discusses a number of kinases present in human beings and other species and their small-molecule inhibitors for treatment of diseases in nononcologic therapeutic fields. In section 2, successful kinase inhibitors already approved for nononcologic diseases are discussed, and in section 3, potential kinase inhibitors that demonstrated efficacy in nononcologic disease models are presented. The opportunities and challenges in developing such SMKIs to meet unmet medical needs are highlighted in section 4.

2. Successful Kinase Inhibitors for Nononcologic Diseases

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2.1. Janus Kinase

Cytokines have indispensable roles in critical cellular functions, including survival, proliferation, inflammation, immunity, and invasion. Recently, there has been increasing interest in modulating the vital intracellular components of cytokine signaling, particularly the Janus kinase (JAK) family,(10) which belongs to a family of intracellular, nonreceptor tyrosine kinases. The JAK family includes four members, JAK1–3 and tyrosine kinase 2 (TYK2), all of which transmit cytokine-mediated signals via the JAK-STAT (signal transducers and activators of transcription) pathway (Figure 2).(11) This pathway influences DNA transcription. Researchers have revealed that JAK2V617F mutation is present in 50–60% of myelofibrosis patients and 95% of polycythemia vera (PCV) patients,(12) paving the way for the development of targeted therapies designed to inhibit overactive JAK signaling. JAK inhibitors have emerged as a feasible treatment option for inflammatory disorders and autoimmune diseases.

Figure 2

Figure 2. JAK/STAT signaling pathway. Various cytokines, such as interleukins, interferons, and neurotrophic factors, bind to their corresponding transmembrane receptors, leading to receptor dimerization. Then, JAKs are recruited to the intracellular region of receptors, resulting in the autophosphorylation of JAKs, which subsequently activates their respective STATs. STATs homodimerize/heterodimerize and then translocate into the nucleus to induce the transcription of various downstream targets associated with inflammation and cancer. IL, interleukin; IFN, interferon.

To date, five JAK inhibitors, ruxolitinib (1), tofacitinib (2), baricitinib (5), upadacitinib (9), and fedratinib (10), have been approved by the U.S. FDA for treatment of autoimmune diseases, inflammatory disorders, and dermatosis. Many other JAK inhibitors are in clinical trials. Oclacitinib, an analogue of tofacitinib, was approved by the U.S. FDA in 2013 as a veterinary medication. This drug is used for treatment of pruritus due to allergic dermatitis and atopic dermatitis in dogs more than 1 year old.
In 2011, the U.S. FDA approved ruxolitinib (1), a JAK inhibitor with selectivity for JAK1 and JAK2 subtypes, to treat intermediate- or high-risk myelofibrosis, and thus, ruxolitinib became the first SMKI with an indication outside of oncology. In 2014, this drug received another approval for PCV patients with an inadequate response to or intolerance for hydroxyurea. Additionally, ruxolitinib has been investigated for use in autoimmune diseases, including plaque psoriasis (PP), alopecia areata (AA), atopic dermatitis, vitiligo, and GVHD. A phase 2 clinical trial of ruxolitinib for PP demonstrated that topical ruxolitinib is effective, with a safe, well-tolerated profile.(13,14) A phase 2 clinical trial of ruxolitinib for AA showed that nine of 12 patients exhibited noteworthy responses to treatment, with no serious adverse effects and an average hair regrowth of more than 90% at the end of the treatment.(15) In the field of oncology, ruxolitinib has been investigated for use in several cancer types such as peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (LBCL), pancreatic cancer, acute myeloid leukemia (AML), glioblastoma, and HER-2-positive breast cancer.
As a pan-JAK inhibitor, tofacitinib (2, CP-690550) inhibits JAK1–3 and TYK2, with Ki values of 0.7, 1.0, 0.2, and 4.4 nM, respectively.(16)Figure 3A shows the binding mode of tofacitinib to JAK3 (PDB 3LXK). This drug demonstrated excellent selectivity against a panel of more than 300 other kinases. Tofacitinib blocks the activity of interleukin (IL)-2, IL-4, IL-15, and IL-21 and interferes with the JAK-STAT signaling pathway. This drug was discovered and developed by the National Institutes of Health (NIH) of the U.S. government and Pfizer and approved by the U.S. FDA in 2012 to treat rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PA), and ulcerative colitis (UC). Currently, tofacitinib is being investigated in clinical trials for AA, vitiligo, and atopic dermatitis. In addition, tofacitinib has demonstrated potential for treatment of obesity because it is capable of converting white fat tissue into brown fat tissue, which is more metabolically active than white fat tissue.(17)

Figure 3

Figure 3. (A) Binding mode of tofacitinib to the ATP-binding site of JAK3 (PDB 3LXK). Tofacitinib forms two hydrogen bonds with Glu903 and Leu905. (B) Binding mode of BMS-986165 to TYK2 JH2 (PDB 6NZP). In addition to hydrophobic interactions, five hydrogen bonds between BMS-986165 and the Arg738, Lys642, Glu688, and Val690 residues can be observed.

Baricitinib (5), which shares the same chemical scaffold as ruxolitinib and was developed by Incyte and Eli Lilly, is an oral drug for treatment of RA.(18) Baricitinib selectively inhibits JAK1 and JAK2, with IC50 values of 5.9 and 5.7 nM, respectively. Baricitinib was approved in Europe in 2017 as a second-line therapy for treatment of moderate to severe active RA in adults. This drug can be used alone or in combination therapy. In 2018, baricitinib was approved by the U.S. FDA to treat moderate to severe active RA in adult patients who did not have a passable response to one or more tumor necrosis factor (TNF) antagonist therapies. In March 2020, baricitinib received a breakthrough therapy designation from the U.S. FDA to treat AA. Beginning in April 2020, this drug has been investigated to treat patients suffering from coronavirus disease 2019 (COVID-19) based on the fact that the anti-inflammatory activity of baricitinib is anticipated to act on the inflammatory cascade related to COVID-19. Currently, this drug is in clinical trials for many disorders other than cancer. Baricitinib did not demonstrate significant safety concerns during the first six months of treatment.(19)
Upadacitinib (9) was approved in 2019 in both the USA and Europe to treat adult patients with moderate to severe active RA. Upadacitinib is a second-generation JAK inhibitor that is selective for the JAK1 subtype (∼60-fold and >100-fold selective for JAK1 over JAK2 and JAK3, respectively). According to the Web site https://www.clinicaltrials.gov/, many clinical trials of this drug are being performed for treatment of different nononcologic diseases, including Crohn’s disease (CD), UC, atopic dermatitis, and PA.
Fedratinib (TG101209, 10) is a semiselective JAK2 inhibitor developed for treatment of myeloproliferative diseases, including myelofibrosis, and this drug is orally available. Having a unique chemical structure compared with other approved JAK inhibitors, fedratinib inhibits JAK2, JAK3, FLT3, and RET (a transmembrane receptor protein–tyrosine kinase) with IC50 values of 6, 169, 25, and 17 nM, respectively. At present, a number of clinical trials of fedratinib for treatment of AML and several nononcologic diseases are being performed. In addition, fedratinib received a priority review designation and an orphan drug designation from the U.S. FDA.
Peficitinib (11, Figure 4) is a pan-JAK inhibitor with IC50 values of 3.9, 5.0, 0.7, and 4.8 nM against JAK1–3 and TYK2, respectively. In 2019, Japan approved peficitinib for treatment of RA.(20) However, clinical trials of this drug for PP, transplant rejection, and UC were discontinued.

Figure 4

Figure 4. Chemical structures of peficitinib, delgocitinib (approved in Japan), and other JAK inhibitors in clinical trials for nononcologic diseases (compounds 1326).

Delgocitinib (12, JTE-052) was developed by Japan Tobacco Inc. In human clinical trials, this drug was revealed to be effective and well tolerated. In January 2020, Japan approved it for treatment of atopic dermatitis. Delgocitinib is a pan-JAK inhibitor with IC50 values of 2.8, 2.6, 13, and 58 nM against JAK1–3 and TYK2, respectively.(21) A phase 2b clinical trial of this drug for chronic hand eczema was completed, but a phase 2 clinical trial for discoid lupus erythematosus was terminated.
Currently, many JAK inhibitors are in clinical trials for both cancer and several nononcologic diseases (Figure 4 and Table 2). Among these JAK inhibitors, cerdulatinib (13, PRT062070), momelotinib (20), pacritinib (21, SB1518), PF-06700841 (23), and TD-1473 (structure undisclosed) are dual or multikinase inhibitors; the remaining ones are specific selective JAK inhibitors. Indeed, compared with pan-JAK inhibitors, data already produced from clinical trials have shown that selective JAK inhibitors have better efficacy and fewer adverse effects because the different inhibition levels of JAKs lead to different cytokine profiles.(10) In August 2020, a selective JAK1 inhibitor, filgotinib (17), was rejected by the U.S. FDA to treat RA, and more clinical data were requested. However, soon after this rejection, filgotinib was approved by both Japan and the European Commission in September 2020. At the same time, positive topline results from a phase 2b/3 trial of filgotinib for moderate to severe active UC were announced by the developers. In China, a phase 1 clinical trial of CS12192 (26), a possible irreversible JAK inhibitor developed by Shenzhen Chipscreen Biosciences, is beginning for RA. This compound selectively inhibits JAK3 (IC50 = 11 nM) over JAK1, JAK2, and TYK2 and demonstrated good therapeutic results in models of adjuvant-induced arthritis and collagen-induced arthritis.(22) Interestingly, this drug has an IC50 value of 162 nM against TANK-binding kinase 1, which was found to play a role in RANKL-induced NF-κB (nuclear factor κ light-chain enhancer of activated B-cells) activation. This helps in making CS12192 superior to other JAK inhibitors in the prevention of bone loss-associated osteoclastogenesis.
Table 2. Clinical Status of JAK Inhibitors with Indications Other than Cancera
drugtargetcompanymost advanced phaseindications of nononcologic diseasesindications of cancer
cerdulatinib (13, PRT062070)SYK, pan-JAKPortola Pharmaceuticalsphase 3vitiligoPTCL, NHL, etc.
decernotinib (14, VX-509)JAK3Vertex Pharmaceuticalsphase 3RA, drug–drug interaction 
PF-06651600 (15)JAK3Pfizerphase 3AA, CD, RA, UC, active nonsegmental vitiligo, impaired kidney function 
abrocitinib (16, PF-04965842)JAK1Pfizerphase 3hepatic impairment, atopic dermatitis, plaque psoriasis, eczema, etc. 
filgotinib (17)JAK1Gilead, Galapagos NVphase 3bRA, CD, UC, AS, SS, COVID-19, PA 
gandotinib (18)JAK2Eli Lillyphase 2myeloproliferative neoplasms, PCV, essential thrombocythemia, myelofibrosis 
itacitinib (19)JAK1Incyte Corporationphase 3GVHD, PP, RA, cytokine release syndromeHodgkin lymphoma, leukemia, pancreatic cancer, NSCLC, etc.
momelotinib (20)JAK1, JAK2, JAK3Ym Biosciences Australiaphase 3myelofibrosis, PCV, thrombocythemiarelapsed/refractory metastatic pancreatic ductal adenocarcinoma, NSCLC
pacritinib (21)JAK2, FLT3Cell Therapeuticsphase 3myelofibrosis, GVHD, COVID-19Leukemias, colorectal cancer, NSCLC, AML, etc.
Solcitinib (22)JAK1GlaxoSmithKlinephase 2SLE, psoriasis 
PF-06700841 (23)TYK2, JAK1Pfizerphase 2UC, CD, alopecia, psoriasis, active nonsegmental vitiligo, PA 
BMS-986165 (24)TYK2Bristol-Myers Squibbphase 3psoriasis, lupus, CD, UC, Crohn’s enteritis 
PF-06826647 (25)TYK2Pfizerphase 2PP, IBD, psoriasis, UC, acne inversa 
CS12192 (26)JAK3Chipscreen Ltd., Chinaphase 1RA 
TD-1473pan-JAKJ&J/Theravancephase 2CD, UC, IBD 
a

Abbreviations used in this table: AA, alopecia areata; AML, acute myeloid leukemia; AS, ankylosing spondylitis; CD, Crohn’s disease; COVID-19, coronavirus disease 2019; IBD, inflammatory bowel disease; GVHD, graft versus host disease; NHL, non-Hodgkin lymphoma; NSCLC, nonsmall cell lung cancer; PA, psoriatic arthritis; PCV, polycythemia vera; PP, plaque psoriasis; PTCL, peripheral T-cell lymphoma; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; UC, ulcerative colitis.

b

This drug was approved in Japan and Europe in September 2020.

In the active conformation, the ATP-binding pockets of the four subtypes of the JAK family are highly conserved, and thus first-generation JAK inhibitors target most JAKs. For example, tofacitinib and ruxolitinib lack subtype selectivity, affecting JAK1/JAK2/JAK3/TYK and JAK1/JAK2, respectively, which results in dose-limiting side effects, such as JAK2 inhibition-driven cytopenias.(23) Recently, novel purinone pan-JAK inhibitors were identified, which have potential for treatment of respiratory diseases via the inhalation route.(24) The best compound demonstrated good selectivity for the JAK family. In addition, in a lipopolysaccharide (LPS) model of airway inflammation treated via the intratracheal route, the best compound demonstrated efficacy, long lung retention time, and low systemic exposure. However, for a variety of autoimmune diseases, there is a great need to develop novel selective JAK inhibitors for safer, more effective, and more convenient treatments. Although this task is challenging, second-generation JAK inhibitors upadacitinib and fedratinib, which have high selectivity, were sent to the market in 2019. The following is another example of the discovery of selective second-generation JAK inhibitors. Vertex Pharmaceuticals screened their compound library against JAK3, and multiple scaffolds exhibiting good inhibitory activity against JAK3 were discovered. Optimization of one of the scaffolds led to the discovery of decernotinib (14), a potent and selective JAK3 inhibitor with a novel chemical structure.(25)
Another strategy for the development of selective JAK inhibitors is targeting possible allosteric sites. For instance, collective evidence has demonstrated that selective inhibition of TYK2 could be a novel promising therapeutic approach with an optimal benefit–safety balance to treat several autoimmune diseases. However, targeting the ATP-binding pocket of TYK2 to identify selective TYK2 inhibitors is very challenging because of the high sequence homology with the JAK family. Promisingly, the unique catalytically inactive pseudokinase domain (JH2) in the JAK family could provide an ideal “allosteric” site for selective TYK2 inhibitor discovery.(26,27) Researchers from Bristol-Myers Squibb recently disclosed the discovery of BMS-986165 (24) as the first JH2-targeting allosteric TYK2 inhibitor, which is undergoing phase 3 clinical trials for psoriasis.(28) This compound inhibits TYK2 JH2 (IC50 value of 0.5 nM) and did not demonstrate inhibitory activities against TYK2 JH1, JAK1, JAK2, or JAK3 at concentrations up to 10 μM. Figure 3B shows the binding mode of BMS-986165 to TYK2 JH2.
On the basis of the inspiring clinical results for already known JAK inhibitors, it is expected that a few will be approved sooner or later for treatment of several different diseases, including cancer. In light of the accumulated medicinal chemistry knowledge, it is also anticipated that more selective and safer JAK inhibitors will be identified in the near future, enter into clinical studies, and finally be sent to the market for a number of diseases.

2.2. Bruton’s Tyrosine Kinase

Bruton’s tyrosine kinase (BTK), which plays a crucial role in B-cell development, is a member of the TEC kinase family of tyrosine kinases. BTK plays key roles in oncogenic signaling and is decisive for survival and proliferation of leukemic cells in several B-cell malignancies (Figure 5), and small-molecule BTK inhibitors have shown excellent antitumor activities. Currently, there is considerable interest in BTK inhibitors as anticancer agents for both B-cell malignancies and solid tumors.(29) Three BTK inhibitors, ibrutinib (3), acalabrutinib (27), and zanubrutinib (28), have been approved by the U.S. FDA for treatment of multiple myeloma, lymphoma, and B-cell leukemia, among other cancer types.

Figure 5

Figure 5. Overview of BTK, SYK, PI3K/AKT/mTOR, MAPK, and related signaling pathways. SRC family kinases, such as Lyn in B/T cells or other cells, phosphorylate ITAM, which then recruits and activates SYK. SYK subsequently phosphorylates several substrates to activate various signaling pathways. SYK activates BTK-PLCγ, which then leads to activation of DAG-PKC and IP3-Ca2+, triggering MAPK signaling, AKT-mediated NF-κB signaling, and calcium mobilization. These pathways are associated with inflammation and cancer. PI3K/AKT/mTOR pathway: CD19, as a coreceptor of B- or T-cell receptors, is activated by Lyn, which then recruits and activates PI3K. PI3K generates PIP3, which recruits BTK and AKT. AKT activation by PDK1 and mTORC2 results in activation of mTORC2 and inhibition of GSK3. These downregulation targets are associated with inflammation, aging, neuropathy, and cancer. MAPK signaling includes the MKK4/7-JNK pathway, MKK3/4/6-p38 pathway, and MEK-ERK pathway. SYK activates the complex SLP65/GRB2/VAV/SOS, leading to activation of the MKK4/7-JNK pathway and MKK3/4/6-p38 pathway, which are associated with inflammation and cancer. PLC, phospholipase; DAG, diacyl glycerol; IP3, inositol triphosphate; IKK, IκB kinase; BCR/TCR, B/T-cell receptor; PIP2, phosphatidyl inositol 4,5-biphosphate; NFAT, nuclear factor of activated T-cells; ITAM, intracellular tyrosine activation; PDK1, 3-phosphoinositide dependent kinase-1; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; GRB2, growth factor receptor-bound protein 2.

In addition, increasing evidence suggests that BTK has multiple roles in mononuclear cells of the human innate immune system, particularly in macrophages and dendritic cells (DCs). This kinase was also recognized as a direct regulator of vital innate inflammatory machinery. BTK inhibitors likely have positive impacts on autoimmune diseases triggered by autoreactive B-cells and immune complex-driven inflammation.(30) Therefore, BTK has received much attention not only to obtain a more detailed understanding of the innate immune system but also to therapeutically modulate this system by developing medical agents. Indeed, BTK is a promising target for the development of drugs to treat various diseases involving B-cell and/or macrophage activation, not only limited to B-cell malignancies but also including several nononcologic diseases, such as RA, multiple sclerosis (MS), asthma, and systemic lupus erythematosus (SLE).(31)
Many BTK inhibitors have been reported.(32) On the basis of their binding mechanisms, BTK inhibitors are divided into reversible and irreversible (or covalent) inhibitors. These two types of inhibitors have their own benefits and different binding modes against BTK (see examples in Figure 6). The kinase domain of BTK contains Cys481 within the ATP-binding pocket in a position conserved in 11 kinases; therefore, Cys481 has been targeted for the development of selective covalent BTK inhibitors. All three BTK inhibitors approved by the U.S. FDA, ibrutinib (3), acalabrutinib (27), and zanubrutinib (28), are irreversible. Currently, many BTK inhibitors are in clinical trials to treat cancer and nononcologic diseases. Table 3 lists many BTK inhibitors with indications other than cancer. Most of them are covalent inhibitors.

Figure 6

Figure 6. (A) Irreversible binding mode of evobrutinib to BTK (PDB 6OMU). The covalent bond formed between Cys481 and evobrutinib is highlighted in purple. Evobrutinib forms three hydrogen bonds with the Thr474, Glu475, and Met477 residues. (B) Reversible binding mode of BMS-986142 to BTK (PDB 5T18). BMS-986142 forms two hydrogen bonds with Met477. For comparison, evobrutinib is depicted as a green stick model after superimposition of the X-ray crystal structure of 6OMU onto 5T18.

Table 3. Clinical Development Status of BTK Inhibitors for Nononcologic Diseasesa
drugapplicantsstatusindications for cancerindications for nononcologic diseases
ibrutinib (3, PCI-32765)Pharmacyclics Inc.approved in 2013CLL, WM, MCL, marginal zone lymphomachronic GVHD
acalabrutinib (27, ACP-196)Acerta Pharmaapproved in 2017MCL, CLL, small lymphocytic lymphomaRA (phase 2), post transplant lymphoproliferative disorder (phase 2), COVID-19
zanubrutinib (28, BGB-3111)BeiGene (Beijing) Co., Ltd.approved in 2019MCL (approved) and several types of cancer in clinical trialsCOVID-19 (phase 2)
rilzabrutinib (29, PRN1008)Principia Biopharmaphase 3b ITP, IgG4-related disease
tolebrutinib (30, SAR442168)Sanofiphase 3b MS
evobrutinib (31)Merck KGaAphase 3b MS, RA, SLE, impaired kidney function
spebrutinib (32, CC-292, AVL-292)Celgene Avilomics Research Inc.phase 2bDiffuse LBCL, CLL, B-Cell CLL, WMRA
tirabrutinib (33, ONO/GS-4059)Gilead Sciencesphase 2b,cNHL, CLLRA, SS
branebrutinib (34, BMS-986195)BMSphase 2d RA, SS, SLE
remibrutinib (35, LOU064)Novartisphase 2b CSU, SS
fenebrutinib (36, GDC-0853)Genentech, Inc.phase 2bB-cell NHL, CLLRA, SLE, lupus, CSU, urticaria
BMS-986142 (37)BMSphase 2b RA, SS
a

Abbreviations used in this table: CLL, chronic lymphocytic leukemia; COVID-19, coronavirus disease 2019; CSU, chronic spontaneous urticaria; ITP, immune thrombocytopenia; GVHD, graft versus host disease; LBCL, large B-cell lymphoma; MCL, mantle cell lymphoma; MS, multiple sclerosis; NHL, non-Hodgkin lymphoma; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; WM, Waldenström’s macroglobulinemia.

b

The most advanced phase.

c

This drug was approved in Japan in 2020 for primary central nervous system lymphoma, WM, and lymphoplasmacytic lymphoma.

d

It is recruiting for patients.

Ibrutinib (3), a potent irreversible BTK inhibitor, covalently targets Cys481 and presents very promising activity against B-cell malignancies.(33) Ibrutinib was developed for treatment of B-cell cancers, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia (WM). This drug was first approved by the U.S. FDA in 2013 and was repurposed in 2017 and further approved for use in chronic GVHD. As a first-generation BTK inhibitor, ibrutinib has exhibited side effects, including bleeding, rash, diarrhea, and atrial fibrillation, which are, in part, attributed to off-target kinase inhibitory-related effects on EGFR and other TEC family kinases.(34)
Acalabrutinib (27, ACP-196, Figure 7), which forms a covalent bond with Cys481 of the protein in the active site and was approved for treatment of MCL in 2017, demonstrated higher selectivity and more potent inhibition against BTK than ibrutinib and an improved safety profile with minimized adverse effects relative to ibrutinib.(35) Acalabrutinib is a second-generation, covalent BTK inhibitor. Currently, more than 55 clinical trials across 40 countries are underway or have been completed. Further studies to better understand and expand the therapeutic uses of acalabrutinib, either alone or in combination with other drugs, are being performed. Almost all of these clinical trials are for cancer, except two, which are for RA and posttransplant lymphoproliferative disorder. Both of these exceptions are in phase 2 clinical trials. The anti-inflammatory effects of BTK inhibitors have raised interest for COVID-19 treatment, and a study managed by the U.S. National Cancer Institute suggests that acalabrutinib may help reduce respiratory distress and inflammation in patients with COVID-19. Currently, AstraZeneca is conducting a 60-person randomized trial of acalabrutinib for COVID-19 treatment.

Figure 7

Figure 7. Chemical structures of BTK inhibitors approved (compounds 3, 27, and 28) or in clinical trials (compounds 2937) for indications other than cancer.

Zanubrutinib (28, BGB-3111), another covalent BTK inhibitor, was approved by the U.S. FDA in November 2019 to treat MCL.(36) Many clinical trials of zanubrutinib for cancer are under way, and a phase 2 clinical trial for COVID-19 is recruiting patients as this Perspective is being written.
Rilzabrutinib (29, PRN1008) [WO 2014039899] is a covalent BTK inhibitor developed by Principia Biopharma and was acquired by Sanofi in September 2020. This compound is currently being evaluated in phase 3 clinical trials for persistent or chronic immune thrombocytopenia (ITP) and is in phase 2 trials for IgG4-related disease.
Tolebrutinib (30, SAR442168), originally developed by Principia Biopharma, is an investigational, oral, brain penetrant, selective small-molecule BTK inhibitor (with an IC50 value of 1.2 nM) [WO 2016196840]. In February 2020, Sanofi claimed that tolebrutinib met the primary endpoint of a phase 2 trial for relapsing MS. In this trial, tolebrutinib significantly reduced disease activity associated with MS as measured by magnetic resonance imaging. Tolebrutinib was well tolerated, with no new safety findings. This drug will potentially be the first disease-modifying therapy to address the source of MS damage in the brain. Sanofi then initiated four phase 3 clinical trials for relapsing and progressive forms of MS.
Evobrutinib (31) is a potent, covalent BTK inhibitor (IC50 = 8.9 nM) with higher kinase selectivity than EGFR and other TEC family kinases, indicating that it may be less likely to have adverse off-target effects.(37) This drug displayed suitable preclinical pharmacokinetic and promising pharmacodynamic characteristics. In addition, evobrutinib demonstrated efficacy in a rat model of RA. Currently, this drug is in clinical trials for a few autoimmune diseases, including SLE, MS, and RA. Figure 6A demonstrates the binding mode of evobrutinib to BTK.
Spebrutinib (32, CC-292, AVL-292), a highly selective, covalent BTK inhibitor, has been used in clinical trials to treat RA and diffuse LBCL, CLL, B-cell CLL, and WM.(38)
Tirabrutinib (33, ONO/GS-4059), a selective covalent BTK inhibitor, has been in phase 1/2 clinical trials for relapsed and refractory mature B-cell malignancies, RA, and Sjögren’s syndrome (SS).(39) In Japan, tirabrutinib was approved in 2020 for treatment of primary central nervous system lymphoma, WM, and lymphoplasmacytic lymphoma.
Branebrutinib (34, BMS-986195) is a covalent, irreversible BTK inhibitor targeting Cys481 that employs BMS-986142 as the lead compound.(40) Branebrutinib has an IC50 value of 0.10 nM against BTK and has a highly desirable selectivity profile with rapid target inactivation in vivo. With its preferable safety and tolerability profile, branebrutinib was sent into clinical evaluations for a few autoimmune disorders, such as RA and SS.
Remibrutinib (35, LOU064) is a potent, highly selective covalent BTK inhibitor developed by Novartis. Because it can bind to an inactive conformation of BTK, this drug displayed precise kinase selectivity.(41) In rat collagen-induced arthritis, remibrutinib demonstrated dose-dependent efficacy and potent in vivo target occupancy. At present, this drug is in phase 2 clinical trial evaluations for SS and chronic spontaneous urticaria (CSU).
Fenebrutinib (36, GDC-0853), currently in clinical development, is a highly potent (Ki = 0.91 nM), selective BTK inhibitor with a noncovalent binding mechanism.(42) Modified from GDC-0834,(43) this drug suppresses B-cell- and myeloid cell-mediated components of disease. In an in vivo rat model of inflammatory arthritis, fenebrutinib showed dose-dependent activity. As the most selective BTK inhibitor disclosed to date, fenebrutinib maintained its inhibitory activity against four different BTK mutants, including Cys481 and Thr474, which are in the active site and in the gatekeeper region, respectively. In ongoing preclinical studies and phase 2 evaluations in patients with several autoimmune disorders, including RA, SLE, urticaria, lupus, and CSU, fenebrutinib has shown highly favorable safety, pharmacokinetics, and pharmacodynamics profiles.(44) For a wide range of immunological disorders, this drug has the potential to become a best-in-class BTK inhibitor. In the field of cancer, phase 1 clinical trials of fenebrutinib have been completed for relapsed or refractory non-Hodgkin lymphoma (NHL) or CLL, and the results have shown generally well-tolerated antitumor activity.(45)
BMS-986142 (37) is a highly potent (IC50 = 0.50 nM), selective, and reversible BTK inhibitor based on carbazole and tetrahydrocarbazole.(46) Interestingly, this drug has two atropisomeric centers, which offer a single, stable atropisomer and lead to improved potency and selectivity as well as a reduction in safety liabilities. Figure 6B shows its binding mode to BTK. Currently, BMS-986142 has advanced into clinical phase 2 studies for RA and SS. Clinical results have indicated that at the doses tested, this drug is well tolerated. Once daily dosing is supported by its pharmacokinetic and pharmacodynamic profiles. In addition, this drug can be coadministered with methotrexate and does not have a pharmacokinetic interaction with methotrexate.(47)
More BTK inhibitors have been reported recently. RN486 (38, Figure 8), designed using structure-based methods, selectively inhibits BTK with an IC50 value of 0.3 nM and is a potential treatment for RA.(48) Compound 39, optimized based on a fragment hit, inhibits BTK with an IC50 value of 4 nM. In a rat model of collagen-induced arthritis, this compound reduced paw swelling in a dose- and exposure-dependent fashion.(49) Compound 40, identified by a scaffold-hopping approach, is a highly selective BTK inhibitor and demonstrated significant efficacy and good ADME and safety profiles in in vivo models; therefore, it was advanced into preclinical studies for RA treatment.(50) Compound 41 was discovered via a structure-hopping strategy from compound 39 and exhibited potent inhibitory effects against both BTKWT and BTKC481S (with IC50 values of 5.3 and 39 nM, respectively). In a rodent collagen-induced arthritis model, compound 41 effectively reduced paw swelling without body weight loss.(51)

Figure 8

Figure 8. Selected recently reported BTK inhibitors in preclinical studies.

For over a decade, many BTK inhibitors have been reported. Among them, three have been sent to the market, and many are in clinical trials for treatment of hematologic malignancies and chronic inflammatory disorders. We expect more BTK inhibitors will be approved for medical uses, especially in the fields of cancer and autoimmune diseases.

2.3. Rho-Associated Protein Kinase

As members of the protein kinase A, G, and C (AGC) family of serine-threonine kinases, rho-associated protein kinases (ROCKs) have critical roles in a wide range of cellular functions, including cell migration, cell contraction and actin organization, neurite elongation and neuronal architecture, angiogenesis, and cytokinesis.(52)Figure 9 shows the ROCK signaling pathway with downstream targets and direct biological regulation. ROCK has two isoforms, ROCK1 and ROCK2, which have 65%, 92%, and 100% identities in amino acid sequence, kinase domains, and ATP-binding pockets, respectively. The structural biology of ROCKs has demonstrated few differences between ROCK1 and ROCK2 at the biochemical and structural levels. ROCK1 and ROCK2 are ubiquitously expressed in most tissues; however, ROCK1 is preferentially enriched in non-nerve tissues, such as the liver, lung, kidney, spleen, and testis, whereas ROCK2 is mainly expressed in the heart and brain, indicating that these two different forms may have different biological activities and functions.

Figure 9

Figure 9. ROCK signaling pathway. As a GTPase, Rho is activated by guanine nucleotide exchange factors (GEFs). Together with GTP, Rho then activates ROCK to phosphorylate various substrates. Among its substrates, ERM, NHE1, adducin, CRMP2, NF-L, MLC, and MARCKS are associated with cellular responses and cytoskeletal regulation. LIMK is involved in the regulation of F-actin stabilization. GEF, guanine nucleotide exchange factors; ERM, ezrin-radixin-moesin; NHE1, sodium hydrogen exchanger 1; CRMP2, myosin light chain phosphatase 2; NF-L, neurofilament protein; MLC, myosin light chain; MLCP, myosin light chain phosphatase; MARCKS, myristylated alanine-rich C-kinase; LIMK, LIM kinases 1 and 2.

ROCK inhibitors may have potential medical applications in a wide range of pathological disorders, such as cancer, diabetes, intracerebral hemorrhage, neurodegenerative diseases (including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD)), pulmonary hypertension, Raynaud’s disease, diabetic retinopathy, and erectile dysfunction.(53) ROCK inhibitors are especially efficacious, alone or in combination with other ocular hypotensive agents, in lowering the intraocular pressure in patients suffering from glaucoma and ocular hypertension, representing a triumph in translational medical research.(54) ROCK inhibitors exhibit neuroprotective activity and even an antifibrotic effect that is beneficial for conventional glaucoma surgery.
Netarsudil (6, AR-13324, Figure 10A) is a novel ROCK/norepinephrine transporter inhibitor with a Ki value of 1 nM against ROCK1 and ROCK2.(55) In animal models, netarsudil engendered durable and considerable intraocular pressure reductions with satisfactory pharmacokinetic and ocular tolerability profiles. Netarsudil was approved in 2017 by the U.S. FDA to reduce elevated intraocular pressure in patients who suffer from open-angle glaucoma or ocular hypertension. Because it explicitly targets the conventional trabecular pathway of aqueous humor outflow, netarsudil is a novel glaucoma medication. Netarsudil has completed clinical trials for the prevention of bullous keratopathy and Fuchs’ endothelial dystrophy. A phase 2 clinical trial for corneal edema has not yet recruited patients.

Figure 10

Figure 10. (A) Chemical structures of ROCK inhibitors approved worldwide. (B) Binding mode of fasudil to ROCK2 (PDB 2F2U). In addition to hydrophobic interactions, three hydrogen bonds and an atypical hydrogen bond (CH···O═C) can be observed between fasudil and the Met172, Asn219, Asp232, and Glu170 residues.

Two ROCK inhibitors, fasudil (42, HA-1077) and ripasudil (43, Figure 10A), were approved for clinical use outside of the USA before the approval of netarsudil. Fasudil is a relatively weak selective ROCK inhibitor, with a Ki value of 0.33 μM against ROCK2.(53,56) As demonstrated in Figure 10B, fasudil binds to the ATP-binding pocket of ROCK2, with the isoquinoline nitrogen atom forming a hydrogen bond with hinge residue Met172 and the sulfonamide moiety pointing toward the catalytic loop.(57) In 1995, Japan and China approved fasudil for treatment of cerebral vasospasm and to ameliorate the cognitive decline that occurs in stroke patients. Additionally, fasudil was found to be efficacious for treatment of pulmonary arterial hypertension in normal mice and showed promise in improving memory, indicating that fasudil could potentially treat age-related or neurodegenerative memory loss. In addition, fasudil showed clinical efficacy as a therapeutic option for pulmonary arterial hypertension.(58) Currently, clinical trial studies of this drug are recruiting patients or are already underway for ALS, Raynaud’s phenomenon, heart failure, atherosclerosis, hypercholesterolemia, and carotid stenosis. A phase 3 clinical trial of combined intravitreal fasudil and bevacizumab for diabetic macular edema was completed in Iran.
Ripasudil, an analogue of fasudil developed from fasudil, is a highly selective and potent ROCK inhibitor (IC50 values of 51 and 19 nM against ROCK1 and ROCK2, respectively). After incorporation of a fluorine atom and chiral attachment of a methyl group in the chemical structure of fasudil, the pharmacological action of ripasudil was noticeably improved, and the ROCK inhibitory activity of ripasudil was much more potent and selective than that of fasudil. In 2014, ripasudil was first approved in Japan and is now being used to treat glaucoma and ocular hypertension.(59) At the time of writing this Perspective, patients are being recruited for a phase 2 clinical trial of ripasudil for treatment of Fuchs’ endothelial dystrophy. Furthermore, ripasudil is under clinical trial to study its ability to treat diabetic retinopathy. In cultured human cells, this drug was shown to promote corneal endothelial cell proliferation, and in a rabbit wound model, it was shown to promote endothelial regeneration and wound healing.(60) In addition, by attenuating activation of conjunctival fibroblasts, this drug has been demonstrated to prevent excessive scarring after glaucoma filtration surgery.(61)
Apart from these three worldwide approved ROCK inhibitors, many ROCK inhibitors have been disclosed. Among them, several have been reported to have potential clinical applications for nononcologic diseases, especially in the field of ophthalmology. In Table 4, six ROCK inhibitors (compounds 4449) that are in clinical studies to treat several different nononcologic diseases are listed. Additionally, a ROCK inhibitor named AT13148 from Astex is in a phase 1 clinical trial for advanced solid tumors. Improvement of the isoform selectivity of ROCK inhibitors might have the advantage of fewer side effects, and such inhibitors could be applied for additional nononcologic diseases, such as CNS disorders, including AD.
Table 4. Clinical Development Status of ROCK Inhibitors for Treatment of Nononcologic Diseasesa
a

Abbreviations used in this table: GVHD, graft versus host disease; IPF, idiopathic pulmonary fibrosis.

Some ROCK inhibitors have demonstrated interesting biological activities. Fasudil and Y-27632 (44) enhanced osteoclastogenesis and accelerated bone healing in rat calvarial defects.(62) The ROCK inhibitors H1152, Y-27632, and fasudil can activate autophagy and proteasome pathways, suggesting that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including AD.(63) A selective ROCK2 inhibitor, BA-1049 (50, Figure 11), is an encouraging treatment for cavernous angioma, which is a disorder without an existing treatment except surgical removal of brain lesions.(64) Compounds with the 4H-chromen-4-one scaffold were reported as ROCK inhibitors.(65) Among them, compound 51 showed excellent kinase selectivity for ROCK1 (IC50 = 14 nM) and ROCK2 (IC50 = 3 nM) against 387 other kinases. This compound inhibited endothelial cell migration in vitro and demonstrated an excellent ability to protect neuronal cells against high glucose-induced damage. In addition, in retinal explants, under the high glucose stress induced in retinal explant models of diabetic retinopathy, compound 51 promoted the regression of vascular vessels, indicating that compound 51 could be a potential lead compound for further study against diabetic retinopathy.

Figure 11

Figure 11. Chemical structure of BA-1049 and compound 51 discussed in the text.

2.4. Spleen Tyrosine Kinase

Spleen tyrosine kinase (SYK), also known as tyrosine protein kinase, is a member of the SYK family of tyrosine kinases. SYK is largely expressed in hematopoietic tissues and is also expressed in a range of other tissues. SYK shares a typical dual SH2 domain that is separated by a linker domain. SYK within B-cells and Zap-70 within T-cells transmit signals from B-cell and T-cell receptors, respectively.(66) In addition to having a crucial role in adaptive immune receptor signaling, SYK mediates various other biological functions, including innate immune recognition, cellular adhesion, osteoclast maturation, vascular development, and platelet activation. This kinase is linked to different inflammatory cells, such as macrophages, which are thought to be the cells responsible for ITP platelet clearance. Abnormal SYK function has been implicated in several instances of hematopoietic malignancies, indicating that SYK inhibition is helpful for treatment of B-cell malignancies. Moreover, SYK inhibition might be a safe and effective way to treat several different immunological diseases.
As the prodrug of the active compound tamatinib (52, R-406, Figure 12A), fostamatinib (8) was granted orphan drug status by the U.S. FDA. Tamatinib is an SYK inhibitor that binds to the ATP-binding pocket with an IC50 value of 41 nM.(67)Figure 12B demonstrates the binding mode of tamatinib to SYK (PDB 3FQS). Because of its ability to inhibit SYK, tamatinib reduces the destruction of platelets by the immune system, which permits an increase in platelet count and therefore decreases the probability of excessive bleeding. On the basis of positive results in a clinical trial program in 2018, fostamatinib was approved by the U.S. FDA to treat adult patients with chronic ITP.(68) This drug has been in clinical trial studies for autoimmune hemolytic anemia, RA, lymphoma, and immunoglobulin A nephropathy. With fostamatinib, an increase in blood pressure has been observed in the clinic, which can be attributed to the fact that tamatinib inhibits a wide range of kinases at higher concentrations.

Figure 12

Figure 12. (A) Structure of tamatinib (52, R-406) and its prodrug fostamatinib (8). (B) Binding mode of tamatinib to SYK (PDB 3FQS). In addition to hydrophobic interactions, two hydrogen bonds, and an atypical hydrogen bond (CH···O═C) can be observed between tamatinib and Ala451 and Glu449.

Very recently, to identify possible medical agents for the pandemic spread of SARS-CoV-2, fostamatinib was screened and repurposed as a candidate for treatment of acute lung injury and respiratory distress syndrome. In a mouse model of acute lung injury, mucin-1 abundance in lung epithelial cells was reduced after fostamatinib administration. In vitro, mucin-1 was removed from the cell surface by fostamatinib treatment. These results were first reported in bioRxiv.(69)
Currently, a number of SYK inhibitors have progressed into clinical evaluations. In addition to the compounds shown in Figure 13, a few SYK inhibitors, including HMPL-523 from Hutchison MediPharma Limited, which has an undisclosed structure, are in clinical trials for nononcologic disorders. HMPL-523 has completed a phase 1 clinical trial for RA, and patients are now being recruited for an ITP trial.

Figure 13

Figure 13. Chemical structures of SYK inhibitors in clinical trials or in trials already being terminated.

Two SYK inhibitors, entospletinib (53, GS-9973) and TAK-659 (54), and two dual SYK/JAK inhibitors, PRT062607 (55) and cerdulatinib (13), are currently being evaluated in the oncology setting.(70) The remaining compounds shown in Figure 13 are in clinical evaluations for patients with immunological disorders. Among them, MK-8457 (56) is a dual inhibitor of SYK and ZAP70 developed by Merck. This compound entered phase 2 clinical trials for RA.(71) However, because of serious infections, the trials were terminated. A phase 1 clinical trial of MK-8457 for blood pressure reduction in hypertensive participants has also been completed.
Entospletinib (53, GS-9973) is a selective SYK inhibitor. This drug is under clinical study for a few hematological malignancies.(72) Unfortunately, its development in inflammatory diseases was prevented by its interaction with proton pump inhibitors and a BID dosing regimen (the clinical trial for GVHD was terminated). As a second-generation selective SYK inhibitor, lanraplenib (57, GS-9876) was developed through modification of entospletinib. This compound has suitable pharmacokinetic properties for once daily administration. Moreover, lanraplenib has no interactions with proton pump inhibitors. At present, this drug has completed clinical evaluations for multiple autoimmune indications, including SLE (phase 2), lupus nephritis (phase 2), and SS (phase 2).(73) A phase 1 clinical trial of chronic GVHD was terminated. In addition, a few clinical trials for cancer, such as AML, have been terminated or are under way.
Gusacitinib (58, Asn002), an SYK inhibitor from Asana BioSciences, is currently in or has completed clinical trials for atopic dermatitis (phase 2), chronic hand eczema (phase 2), dermatitis eczema basal (phase 1), and basal cell nevus syndrome and basal cell carcinoma (phase 2).(74) Gusacitinib reversed the lesional skin transcriptome toward a nonlesional phenotype. In addition, this drug rapidly and significantly suppressed key inflammatory pathways implicated in atopic dermatitis pathogenesis. Therefore, gusacitinib might be an effective novel therapeutic agent for moderate to severe atopic dermatitis. Clinical trials for several cancer types were terminated, but one in adult sick persons suffering from low-risk nodular basal cell carcinoma is still underway (NCT02550678).
GSK2646264 (59) from GlaxoSmithKline is an SYK inhibitor that completed a phase 1 clinical trial for cutaneous lupus erythematosus and urticaria in 2019.(75)
SYK regulates amyloid-β production via Tau phosphorylation and NF-κB-dependent mechanisms by regulating the activation of glycogen synthase kinase 3β. SYK inhibition can interrupt Tau hyperphosphorylation, pathological amyloid-β accumulation, and neuroinflammation in AD. Therefore, SYK is a promising drug target to inhibit the development of the pathological lesions that define AD.(76) Nilvadipine (60), an L-type calcium channel antagonist used for treatment of hypertension and chronic major cerebral artery occlusion, inhibits SYK. This compound has been demonstrated to adjust Tau phosphorylation and amyloid-β production and thus has been suggested as a possible medication for AD.(76) At present, this compound is in phase 3 clinical trials for AD.
SYK has been validated as a target for the development of drugs to treat immunological diseases, and clinical and preclinical results have indicated that SYK inhibitors that are highly selective or can purposely tune broader inhibitory activity against many kinases are desirable.(77)

2.5. Mammalian Target of Rapamycin

In the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, mammalian target of rapamycin (mTOR, also named mechanistic target of rapamycin) is a downstream effector (see Figure 5). The C-terminal domain of mTOR shares strong homology with the catalytic domain of PI3K; therefore, mTOR is recognized as a member of the PI3K-related kinase family. mTOR is ubiquitously expressed throughout the body and is the fundamental component of two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. As a serine/threonine protein kinase, mTOR regulates metabolism, cell growth, and protein synthesis in response to nutrients, growth factors, stress, and energy levels.(78)
Overactivation of mTOR signaling is related to tumor initiation and development, and mTOR activity has been found to be deregulated in many cancer types, such as lung, breast, prostate, brain, bladder, melanoma, and renal carcinomas.(79) mTOR inhibitors can be used as anticancer agents. Indeed, a few rapalogues (rapamycin and its analogues, not typical small molecules) have been approved as anticancer agents, and several small-molecule mTOR inhibitors, including sapanisertib and vistusertib, have been used in clinical studies for cancer treatment. In addition, mTOR is involved in age-related diseases, such as aging, cataracts, type 2 diabetes mellitus, cardiovascular diseases, and neurodegenerative diseases, for example, AD and ALS.(80)
The first-generation mTOR inhibitors are rapalogues. In clinical trials, such compounds have demonstrated antitumor activity against different tumor types.(81) By reducing sensitivity to IL-2 through mTOR inhibition, sirolimus (61, rapamycin, Figure 14A), a macrolide from bacteria, inhibits activation of B-cells and T-cells. Sirolimus is an allosteric inhibitor of mTORC1 and an autophagy inducer. Figure 14B shows the binding mode of sirolimus to mTOR (PDB 4DRH). The antiproliferative effects of sirolimus may play a role in cancer treatment, and this compound has been evaluated in more than 200 clinical trials for several cancer types, such as brain and CNS tumors, and has been approved for a number of cancer treatments. However, compared with control drugs, a higher rate of fatal adverse events has been found in cancer patients administered sirolimus, which is similar to findings related to its analogues, such as everolimus (62, RAD001) and temsirolimus (63, CCI-779, a prodrug of sirolimus).(82) Similar therapeutic effects have been found with other rapalogues; however, they have better hydrophilicity and can be administered orally and intravenously.

Figure 14

Figure 14. (A) Chemical structure of sirolimus and its analogues approved for medical uses. (B) Binding mode of sirolimus to mTOR (PDB 4DRH). Sirolimus forms extensive hydrophobic interactions with surrounding residues, and four hydrogen bonds between this drug and the Asp68, Gly84, Ile87, and Tyr113 residues can be observed.

In the field of nononcologic diseases, rapamycin has immunosuppressant functions in humans; therefore, it is particularly beneficial to prevent the rejection of kidney transplants and was approved in 2009 for the prevention of organ transplant rejection. Furthermore, in 2015, this drug was further approved to coat coronary stents and for treatment of lymphangioleiomyomatosis, a rare, progressive, and systemic disorder that characteristically leads to cystic lung destruction. In addition, sirolimus is used to treat venous malformations. Sirolimus has also shown promise in treating tuberous sclerosis, longevity, and neurodegenerative diseases, among others. In 2018, a phase 2 clinical trial named RAP-ALS with 63 ALS patients was started in Italy.(83)
From 2009 to 2016, everolimus (62) was approved by the U.S. FDA for several cancer types. This drug was further approved for the prevention of organ rejection after renal transplantation (in 2011) and liver transplantation (in 2013) and for tuberous sclerosis complex (TSC)-associated partial-onset seizures (in 2018).
Second-generation mTOR inhibitors are ATP-competitive inhibitors that act selectively on mTOR or on both mTOR and PI3K (dual PI3K/mTOR inhibitors). These two types of mTOR inhibitors have provided promising preclinical results in the field of oncology, and several such compounds, including apitolisib, dactolisib, gedatolisib, and sapanisertib, are in clinical trials for cancer treatment. At the same time, a few of them have been reported to be implicated in nononcologic diseases.
TSC is a disease with overactivated mTOR signaling. For seizure reduction in patients with TSC, clinical results of everolimus have revealed that mTOR inhibitors have therapeutic value in CNS disorders. Considering that everolimus is a partial inhibitor of mTOR function and starting from an in-house purine-based compound, scientists at Novartis developed a novel mTOR inhibitor (64, Figure 15) with enhanced properties that is appropriate for CNS disorders. This brain penetrant compound selectively targets mTOR, exhibited good brain exposure, and remarkedly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene.(84)

Figure 15

Figure 15. Reported mTOR inhibitors demonstrating efficacy in nononcologic disease models.

CZ415 (65) is a highly potent, selective ATP-competitive mTOR inhibitor. In a semitherapeutic collagen-induced arthritis mouse model, this compound exhibited efficacy.(85) Chloroquine (66) is an antimalarial drug and autophagy inhibitor. This well-known drug has been studied as an antiviral agent to treat Kaposi sarcoma-associated herpesvirus (KSHV). Through inhibition of activation of the mTOR and p38 MAPK (mitogen-activated protein kinase) pathways with an IC50 value of 0.27 μM, this compound repressed the lytic replication of KSHV.(86) Chloroquine and hydroxychloroquine have recently been used in clinical studies for treatment of COVID-19. Chloroquine has a quinoline core, and many mTOR inhibitors contain this fragment.
Torin 1 (67) is a selective mTOR inhibitor. Torin 1 exhibited 1000-fold and 100-fold selectivity for mTOR over PI3K and 450 other protein kinases, respectively. At concentrations of 2 and 10 nM, this compound can inhibit the phosphorylation of mTORC1 and mTORC2 substrates in cells.(87) In a U87MG xenograft model, Torin 1 was effective at a dose of 20 mg/kg, and in tumor and peripheral tissues, this compound exhibited good pharmacodynamic inhibition of downstream effectors of mTOR. Recently, it was reported that Torin 1 can intervene in mTOR signaling in the insular cortex to alleviate neuropathic pain.(88) Torin 2 (68), which has improved stability and prolonged half-life in mouse microsomes, was obtained by simplifying Torin 1. Torin 2 has an EC50 value of 25 nM against mTOR and an IC50 value of 37.1 nM against mTORC1.(89) Preclinical studies of Torin 2 have been carried out for various cancer types. This compound has antimalarial activity and can inhibit the replenishment of parasitophorous vacuole membrane proteins in the Plasmodium liver stage.(90) P529 (69, Palomid 529) inhibits mTORC1 and mTORC2 simultaneously.(91) P529 demonstrated a good performance in prostate cancer and could enhance sensitization to radiotherapy and some drugs. No concerns for ocular or systemic toxicity were associated with subconjunctival injections of P529 to treat neovascular age-related macular degeneration.(92)
Rapalogues are selective allosteric mTORC1 inhibitors and are unable to inhibit mTORC2. mTOR inhibitors that simultaneously inhibit both mTORC1 and mTORC2, such as Torin 2 and P529, are expected to expand the therapeutic potential of mTORC inhibitors. Indeed, many selective mTOR inhibitors have been reported, but most, for example, onatasertib,(93) have been evaluated in a wide range of malignancies. Considering the importance of selective mTOR inhibition in other diseases, it is anticipated that more mTOR inhibitors will be explored to determine their potential in these fields.

3. Potential Kinase Inhibitors for Nononcologic Diseases

ARTICLE SECTIONS
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3.1. Phosphoinositol 3-Kinases

Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH in the inositol ring of phosphoinositides and play vital roles in critical cellular functions, including cell growth, differentiation, proliferation, survival, migration, and intracellular trafficking.(94) PI3Ks have eight identified members, which are divided into class I, class II, and class III PI3Ks. On the basis of the type of regulatory subunit, class I PI3Ks, which are the most studied, are further subdivided into two subclasses: IA (including PI3Kα, β, and δ) and IB (PI3Kγ). PI3Kα and PI3Kβ are ubiquitously expressed, while PI3Kδ and PI3Kγ are expressed in epithelial cells, the hematopoietic system, and the CNS.
The PI3K pathway is one of the most extensively studied pathways for cancer therapeutics (see Figure 5).(95) All four class I PI3Ks are implicated in cancer.(96) Four drugs, idelalisib (a PI3Kδ inhibitor), copanlisib (a pan-PI3K inhibitor), duvelisib (a dual PI3Kδ/γ inhibitor), and alpelisib (a PI3Kα inhibitor), were approved in 2014, 2017, 2018, and 2019, respectively, for treatment of several cancer types.
Additionally, deregulation of the PI3K pathway has implications in many nononcologic diseases.(97) Increasing evidence has revealed that PI3Kα is related to obesity and diabetes, PI3Kβ is related to thrombosis, both PI3Kγ and PI3Kδ are related to RA and asthma, PI3Kδ is implicated in activated PI3Kδ syndrome (APDS), and PI3Kγ is implicated in IPF. Genetic inactivation of PI3Kα and PI3Kβ leads to embryonic lethality in mice. PI3Kγ and PI3Kδ have been identified as promising targets for the development of drugs to treat inflammatory diseases and immunomodulatory disorders.
To develop medical agents with adequate therapeutic indexes, specifically for nonlife-threatening diseases, PI3K inhibitors with good isoforms and wide kinase selectivity are of great interest. A wealth of effort by pharmaceutical companies and academic groups has been devoted to identifying novel isoform-selective, pan PI3K inhibitors, or dual (such as PI3K/HDAC and PI3K/mTOR) inhibitors, leading to four marketed anticancer drugs and at least 38 clinical candidates.(97) The primary indications of these candidates (for instance, umbralisib) are oncology but also include nononcologic diseases, such as chronic obstructive pulmonary disease (COPD)/asthma and primary immunodeficiency disease (Table 5). However, no PI3K inhibitors have yet been approved for indications other than cancer, although a few are in clinical trials. To date, dramatic successes have been achieved with selective PI3Kδ inhibitors.
Table 5. PI3K Inhibitors Currently in Clinical Trials for Nononcologic Diseasesa
drugtargetapplicantsmost advanced phasenononcologic diseases in clinical trials
nemiralisib (70, GSK2269557)PI3KδGlaxoSmithKlinephase 2COPD, asthma, APDS, lymphadenopathy, bronchiectasis
GSK2292767 (71)PI3KδGlaxoSmithKlinephase 1asthma
seletalisib (72)PI3KδUCB Celltechphase 3APDS/PASLI, SS
leniosilib (73, CDZ173)PI3KδNovartisphase 3primary immunodeficiency disease
RV-1729 (74)PI3Kδ/γRespiVertphase 1COPD/asthma
RV-6153 (75)PI3Kδ/γRespiVertphase 1COPD/asthma
AZD8154PI3Kδ/γAstraZenecaphase 1asthma
a

Abbreviations used in this table: APDS, activated PI3Kδ syndrome; COPD, chronic obstructive pulmonary disease; PASLI, p110 delta activating mutation causing senescent T-cells, lymphadenopathy and immunodeficiency; SS, Sjögren’s syndrome.

Nemiralisib (70, GSK2269557, Figure 16), developed by GlaxoSmithKline, is a selective PI3Kδ inhibitor currently in phase 2 for treatment of asthma, COPD, APDS, bronchiectasis, and PASLI (p110 δ activating mutation causing senescent T-cells, lymphadenopathy, and immunodeficiency).(98) Nemiralisib inhibits PI3Kδ, PI3Kα, PI3Kβ, and PI3Kγ , with IC50 values of 0.126, 5010, 1580, and 6310 nM, respectively. GSK2292767 (71), an analogue of GSK2269557, is a highly potent and selective PI3Kδ inhibitor that has excellent cellular activity.(98) GSK2292767 inhibits PI3Kδ, PI3Kα, PI3Kβ, and PI3Kγ, with IC50 values of 0.08, 500, 630, and 500 nM, respectively, and has been developed for asthma and COPD. In 2017, a phase 1 clinical trial of this compound in healthy smokers was completed. The selectivity of these two analogues toward PI3Kδ can be attained by taking advantage of the conformational flexibility and sequence diversity of the active site residues that have no contacts with ATP.(99)Figure 17A demonstrates the binding mode of nemiralisib to PI3Kδ (PDB 5AE8). Figure 17B shows that Thr750 (in yellow ball and stick mode), one of the key residues in PI3Kδ, determines the selectivity of nemiralisib and GSK2292767. In PI3Kα, PI3Kβ, and PI3Kγ, the residues corresponding to Thr750 are larger and positively charged (Arg770, Lys771, and Lys802), which would lead to clashes with nemiralisib and GSK2292767 when binding.

Figure 16

Figure 16. Chemical structures of PI3K inhibitors in clinical trials for nononcologic diseases.

Figure 17

Figure 17. (A) Binding mode of nemiralisib to PI3Kδ (PDB 5AE8). In addition to hydrophobic interactions, nemiralisib forms three hydrogen bonds with the Asp787, Glu826, and Val827 residues. (B) Key residues determining the selectivity of nemiralisib among PI3Kα, β, γ, and δ.

Seletalisib (72)(100) and leniosilib (73),(101) developed by UCB Celltech and Novartis, respectively, are two oral, selective PI3Kδ inhibitors. Both of these drugs have entered phase 3 clinical trials for APDS/PASLI and a phase 2 clinical trial for SS and have received orphan drug designations from the U.S. FDA.
Dual PI3Kδ/γ inhibitors are being developed for use in oncology and in respiratory diseases. RV-1729 (74) and RV-6153 (75) are two dual PI3Kδ/γ inhibitors from RespiVert Ltd. These two compounds have completed phase 1 clinical studies in respiratory diseases, asthma, and COPD. A phase 1 study has been initiated for another dual PI3Kδ/γ inhibitor, AZD8154 (structure not yet disclosed), for treatment of asthma.
Different selective PI3Kδ inhibitors have demonstrated similar adverse event profiles in clinical trials.(102) Thrombocytopenia, neutropenia, transaminitis, anemia, pneumonia/pneumonitis, and diarrhea/colitis are the most commonly observed adverse events. Dual PI3Kγ/δ inhibitors may have toxicity profiles similar to those of selective PI3Kδ inhibitors. However, selective PI3Kγ inhibitors may have a potentially favorable toxicity profile. Therefore, selective PI3Kγ inhibitors are of great interest for treatment of inflammation, autoimmune diseases, and cardiovascular diseases. However, because of the high sequence similarity between isoforms, selective PI3Kγ inhibitors are difficult to identify. Currently, a selective PI3Kγ inhibitor, IPI-549, is in a phase 1 trial for immuno-oncology;(103) no selective PI3Kγ inhibitors have yet been in clinical trials for nononcologic diseases.
Recently, some PI3K inhibitors with interesting biological effects in nononcologic disease models have been disclosed. Compound 76 (Figure 18), a pan-PI3K inhibitor, was reported to improve mouse lung function, slow the progression of pulmonary fibrosis, and have promising therapeutic potential for IPF treatment.(104) However, because of the benefits of selective PI3K inhibitors, great interest has been focused on developing novel and selective PI3K inhibitors. Compound 77 was reported as a selective brain penetrant PI3Kγ inhibitor and showed efficacy in murine experimental autoimmune encephalomyelitis.(105) LAS195319 (78) has an IC50 value of 0.5 nM and is a potent selective PI3Kδ inhibitor. This inhaled compound has been proposed for treatment of COPD and severe asthma.(106) Compound 79 is a potent, selective, and efficacious PI3Kδ inhibitor that demonstrated high efficacy in a mouse collagen-induced arthritis model.(107) Compound 80 has good PI3Kδ subtype selectivity, promising oral bioavailability, and inspiring in vivo efficacy for treatment of respiratory disease.(108) AM-8508 (81) is a potent, selective PI3Kδ inhibitor that is orally bioavailable. In a keyhole limpet hemocyanin study in rats, this compound exhibited promising efficacy.(109)

Figure 18

Figure 18. Chemical structures of recently reported PI3K inhibitors demonstrating interesting biological effects in nononcologic disease models.

In the near future, it is expected that more PI3K inhibitors, especially selective PI3Kδ inhibitors, will be approved and reach the market for treatment not only of cancer but also of nononcologic diseases, including arthritis, asthma, and COPD.

3.2. PI3K/AKT/mTOR Pathway

As one of the major cellular signaling pathways and a vital intracellular signaling pathway in regulating cell cycle, the PI3K/AKT/mTOR pathway directly participates in several cellular processes, such as proliferation, cell growth, metabolism, and angiogenesis (see Figure 5).(110) This pathway has been found to be dysregulated in many fatal diseases, such as cancer and metabolic, cardiovascular, and neurological disorders. In addition, this pathway is involved in the development of osteoarthritis, a complicated degenerative disease that affects whole joint tissue.(111) The PI3K/AKT/mTOR pathway is a promising therapeutic target for anticancer drug development. PI3K/AKT/mTOR signaling pathway inhibitors include single-component (PI3K inhibitors, AKT inhibitors and mTOR inhibitors) and dual inhibitors, such as dual PI3K/mTOR inhibitors.
Monotarget agents designed to act on individual targets (such as PI3K in the PI3K/AKT/mTOR pathway) are usually inadequate for multigenic diseases such as cancer. Combination therapy or multitarget agents are more effective than monotarget agents. However, combination therapy is limited by dose-limiting toxicities and drug–drug interactions. In addition, the cost of combination therapy is greater than that of a single agent. Dual or multitarget agents may overcome these drawbacks, with the advantages of avoiding the different metabolism, pharmacokinetics, and bioavailabilities of each component in combination therapy. The risk of possible drug–drug interactions would be avoided, and the dosing regimen would be greatly simplified to enhance compliance and therapeutic efficacy. Nevertheless, the critical challenge for dual or multitarget agents is how to design a drug with the desired balance of two (or more) activities in concert with optimizing the ADME-PK properties and safety profile.(112)
Dual PI3K/mTOR inhibitors may effectively prevent PI3K signaling cascade transduction, overcome feedback loops, and block PI3K-independent mTOR activation; hence, the discovery and development of dual PI3K/mTOR inhibitors would provide beneficial therapeutic intervention strategies in cancer treatment,(113) and many such dual inhibitors have been reported; for example, gedatolisib (PF-05212384) and PF-04691502 are in clinical trial studies for cancer treatment.(114)
A representative dual PI3K/mTOR inhibitor is omipalisib (82, GSK2126458, Figure 19A), which inhibits PI3Kα/β/γ/δ and mTORC1/2 at picomolar concentrations and has been in a phase 1 clinical trial for advanced solid tumors in combination therapy with trametinib (GSK1120212, a MEK inhibitor).(115)Figure 19B displays the binding mode of omipalisib to PI3Kγ. Both PI3Ks and mTOR play roles in the pathogenesis of IPF. Recently, omipalisib was repositioned from oncology to IPF, and an early clinical trial demonstrated that this drug was reasonably well tolerated and produced important downstream effects on key intracellular signaling in the fibrotic lung at tolerated doses, supporting further assessment of PI3K/mTOR inhibition as a novel medical intervention for IPF therapeutics.(116)

Figure 19

Figure 19. (A) Chemical structure of omipalisib (GSK2126458). (B) Binding mode of omipalisib to PI3Kγ (PDB 3L08). Two hydrogen bonds are formed between omipalisib and the Ser806 and Val882 residues. In addition, a bridged hydrogen bond and one atypical CH···O═C hydrogen bond can be observed.

To explore their potential clinical uses for both cancer and nononcologic diseases, dual PI3K/mTOR inhibitors with high potency, few side effects, and low toxicity are urgently needed. In addition, we need to further explore the PI3K/AKT/mTOR pathway for more medical applications. For example, it was reported that activated PI3K/AKT signaling with increased or reduced mTOR and GSK3β activity influences the wound repair process; therefore, dual PI3K/AKT inhibitors may have the potential to treat diabetic wound healing.(117) In diseases of pregnancy, the AKT/mTOR signaling pathway plays an important role in human fetoplacental vascular insulin resistance.(118) Proof of these concepts needs to be further explored by using PI3K/mTOR, PI3K/AKT, and AKT/mTOR dual inhibitors.

3.3. FMS-like Tyrosine Kinase 3

As a type III receptor tyrosine kinase, FMS-like tyrosine kinase 3 (FLT3) is mainly expressed in early hematopoietic progenitor cells, facilitating hematopoietic expansion. Once the FLT3 ligand, a member of a small family of hematopoietic growth factors, binds to FLT3, and FLT3 is autophosphorylated and activated, mediating downstream signaling pathways, such as RAS/MAPK, JAK/STAT5 and PI3K/AKT, to promote myeloid cell survival, proliferation, and differentiation (Figure 20).(119) FLT3 is frequently mutated in AML, and nearly 30% of AML patients exhibit FLT3 mutations; thus, inhibition of FLT3 is an effective strategy to treat AML.(120) FLT3 is also involved in the development and function of DCs, which regulate immune responses as the main antigen-presenting cells. DCs can induce activation of T cells associated with the immune response and drive T cell differentiation toward specific phenotypes by secreting several cytokines.(121) Drugs targeting FLT3 have the potential to treat psoriasis through interference with DCs. Moreover, the FLT3 ligand is highly expressed at the site of inflammation in human RA, promoting the inflammation process and increasing the likelihood of tissue destruction. Therefore, FLT3 has been regarded as a therapeutic target for inflammatory diseases, including RA.(122) In addition, the FLT3 ligand is expressed by hematopoietic cells at the site of nerve injury. One study showed that FLT3 activation induced by intrasciatic nerve injection of FLT3 ligand results in pain hypersensitivity, suggesting that FLT3 inhibition could be a potential strategy for relieving pain caused by nerve injury.(123)

Figure 20

Figure 20. FLT3 signaling pathway. FLT3 recruits PI3K via the adaptor protein GRB2 or by forming multiprotein complexes. Subsequently, PI3K activates the MAPK pathway and PI3K/AKT/mTOR pathway, as shown in Figure 5.

Midostaurin (7), a semisynthetic derivative of staurosporine, is a multitarget kinase inhibitor that showed good potency over 15 kinases, with IC50 values less than 0.1 μM. The major kinase targets include FLT3, phosphoinositide-dependent protein kinase 1, vascular endothelial growth factor (VEGF), PDGFR, KIT proto-oncogene receptor tyrosine kinase, and kinase domain receptor.(124) Because of its activity against FLT3, it was evaluated in clinical trials for adult patients who were newly diagnosed with AML and showed an FLT3 genetic mutation. Interestingly, based on its KIT inhibitory activity, midostaurin was also approved for treatment of a nononcologic disease, advanced systemic mastocytosis, in which a KIT D816 mutation was found in approximately 90% of patients.(125) In addition, midostaurin has been evaluated for diabetes-related macular degeneration, supported by its inhibitory activity against VEGF and angiogenesis.(126)
SB1578 (83, Figure 21), a multikinase inhibitor targeting FLT3 (IC50 = 62 nM), JAK2 (IC50 = 46 nM), and colony-stimulating factor 1 receptor (CSF1R, IC50 = 69 nM), showed promising results via oral administration in a collagen-induced arthritis model and a rodent adjuvant-induced arthritis model of RA. SB1578 has entered phase 3 clinical trials for myelofibrosis, GVHD, COVID-19, and several cancer types. As discussed in section 2.1, JAK2 has an important role in regulating proinflammatory cytokine signaling associated with the pathogenesis of RA. CSF1R is a tyrosine kinase receptor, and its expression is increased in pathologies of RA. Therefore, simultaneous blockade of these three kinases could be an effective strategy for RA treatment. SB1578 was designed by optimizing the structure of SB1518 (a JAK2/FLT3/TYK2 inhibitor, pacritinib, 21) and SB1317 (84, a CDK/JAK2/FLT3 inhibitor) to achieve improved solubility and selectivity over CDK, which plays a critical role in oncology applications.(127) SB1578 demonstrated potent oral efficacy in a murine collagen-induced arthritis model of RA, supporting the notion that SB1578 could be a potential method for treatment of autoimmune diseases and inflammatory disorders such as psoriasis and RA. SB1578 reached phase 1 clinical trials in healthy volunteers in 2010, but no advanced clinical trials are available to date.

Figure 21

Figure 21. Chemical structures of a few FLT3 inhibitors discussed in the text.

A series of 1-(4-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tertbutyl)isoxazol-3-yl)urea derivatives have been reported as FLT3 inhibitors for psoriasis treatment.(128) Previously, this series of compounds, for example, compound 85, were dual FLT3/VEGFR2 inhibitors used for AML, but they also exhibited certain antipsoriatic effects in K14-VEGF transgenic homozygous mice.(129) On the basis of compound 85, a potent FLT3 inhibitor (compound 86, IC50 = 6 nM against FLT3) was discovered and found to exhibit significant antipsoriatic activity in a K14-VEGF transgenic mouse model. After the last administration, there was no recurrence in mice 15 days later. In vitro experiments indicated that compound 86 could reduce DC products and inhibit cytokine secretion by DCs by blocking the FLT3 signaling pathway. Therefore, the authors suggested that compound 86 might be a candidate for psoriasis treatment.
SKLB4771 (87) is a potent FLT3 inhibitor (IC50 = 10 nM) with good kinase spectrum selectivity.(130) When used for psoriasis-like symptoms of disease in mice, this compound almost completely cured this disease without obvious toxicity. Studies have demonstrated that SKLB4771 leads to a significant decrease in pDC and mDC levels and activation both in vitro and in vivo. In addition, subsequent T-cell cascade reactions regulated by Th1/Th17 pathways were also reduced. These results revealed that specific targeting of FLT3, or hence direct interference with DCs, may be a novel strategy for psoriasis treatment.

3.4. Apoptosis Signal-Regulating Kinase 1

As a serine/threonine kinase and a part of the MAPK pathway, apoptosis signal-regulating kinase 1 (ASK1, also named mitogen-activated protein kinase 5) belongs to the mitogen-activated protein kinase kinase kinase (MAP3K) family.(131) Through phosphorylation and activation of downstream MAP2Ks, ASK1 activates the c-Jun N-terminal kinase (JNK) and p38 MAPK signaling cascades in response to different stressors, including saturated free fatty acids, TNF-α, and lipopolysaccharide (Figure 22). ASK1 is known to regulate cell proliferation. Inhibition of ASK1 results in decreased activation of hepatic macrophages and protects against both hepatic inflammation and fibrogenesis. Several lines of evidence have indicated that aberrant ASK1 signaling leads to several human diseases, such as cancer, cardiovascular disease, diabetes, RA, nonalcoholic fatty liver disease, neurodegenerative disease, infections, and MS.(132,133)

Figure 22

Figure 22. Role of ASK1 in the MKK4/7-JNK and MKK3/4/6-p38 signaling pathways. ASK1 is activated by inflammatory cytokine signaling and oxidative stress, which then leads to activation of MKK4/7 and MKK3/4/6, triggering the JNK and p38 signaling pathways. RTKs, receptor tyrosine kinases; TRADD, tumor necrosis factor receptor-associated death protein; Daxx, death domain-associated protein; TRAF2, TNF receptor-associated factor 2.

ASK1 was identified as a promising target for therapeutic applications; therefore, much attention has been given to the development of ASK1 inhibitors, and many ASK1 inhibitors have been reported.(134) Among them, selonsertib (88, GS-4997, Figure 23) has advanced into phase 2 clinical trials for alcoholic hepatitis, diabetic kidney disease, nonalcoholic steatohepatitis, pulmonary arterial hypertension, and nonalcoholic fatty liver disease and demonstrated positive results, alone or in combination with other drugs.(135−138)

Figure 23

Figure 23. Chemical structures of reported ASK1 inhibitors discussed in the text.

On the basis of selonsertib, a combined structure-based and compound deconstruction approach was employed, and a novel series of potent ASK1 inhibitors with ideal physiochemical properties and efficiencies were rapidly produced.(139) The best compound, 89, was shown to reduce infarct size in the Langendorff perfused ex vivo heart model.
An X-ray cocrystal structure of selonsertib binding to ASK1 was published (Figure 24, PDB 6OYT), and structural analysis resulted in the design and synthesis of many novel macrocyclic inhibitors following a deconstruction–cyclization approach.(140) Compound 90 showed good cellular potency and pharmacokinetic properties with excellent brain exposure. The authors claim that these ASK1 inhibitors might be useful tools to further understand the role of ASK1 inhibition in neurodegenerative disease.

Figure 24

Figure 24. Binding mode of selonsertib to ASK1 (PDB 6OYT). Selonsertib forms two hydrogen bonds with Lys709 and Val757. In addition, it has extensive hydrophobic interactions with surrounding residues, including Leu686, Val694, Ala707, Met754, Val757, and Leu810.

More brain penetrant ASK1 inhibitors have been reported. MSC2032964A (91) selectively inhibits ASK1 with an IC50 value of 90 nM. It was tested in an in vivo autoimmune encephalomyelitis model (an animal model of MS) and found to attenuate the severity of encephalomyelitis without affecting the proliferation capability of T-cells, suggesting that the TLR-ASK1-p38 pathway in glial cells might be a promising drug target for autoimmune demyelinating diseases, such as MS.(141) K812 (92), is a specific ASK1 inhibitor (IC50 = 6 nM) that prolonged survival of transgenic mice with ALS, a fatal neurodegenerative disease.(142) K812 alleviates ALS disease progression by inhibiting activation of ASK1 in the spinal cord. GS-444217 (93), a selective, orally available ASK1 inhibitor, dose-dependently reduced pulmonary arterial pressure in animal models.(143)

3.5. Receptor Interacting Protein Kinases

Receptor interacting protein kinases (RIPKs) are a group of serine/threonine protein kinases. This family has seven members, RIPK1–RIPK7, all of which share a fairly conserved kinase domain but have diverse nonkinase regions and have emerged as essential sensors of intracellular and extracellular stresses.(144) RIPKs have vital roles in inflammation, other immune responses, and cell death-inducing processes.(145,146) As central inducers of necroptosis and apoptosis activation via caspase interactions, both RIPK1 and RIPK3 play well-established roles.(147) RIPK2 has been recognized as a valid therapeutic target to develop medical agents to treat a variety of autoimmune diseases. RIPK4 is less well studied but was identified as the causative gene in popliteal pterygium syndrome, an inherited disease affecting the face, limbs, and genitalia.(148) RIPK6 and RIPK7 (also named leucine-rich repeat kinase 1 and leucine-rich repeat kinase 2, respectively) have been associated with the pathogenesis of PD (see section 3.12).

3.5.1. Receptor Interacting Protein 1 Kinase

RIPK1 is a vital upstream regulator of inflammation and necroptosis, and the association of RIPK1 with various pathologies, including inflammatory, ischemic injury, neurodegenerative, and oncogenic diseases, has been studied.(149) RIPK1 is an inspiring therapeutic target for the development of drugs to treat inflammatory and neurodegenerative diseases, which are significant unmet medical needs. Currently, the RIPK1 inhibitor GSK2982772 (94, Figure 25) is undergoing phase 2a clinical trials in psoriasis, UC, and RA. This drug is ATP-competitive (IC50 value being 1.0 nM); however, it has a specific binding mode (Figure 26), which suggests that it is an allosteric inhibitor (type III class).(150) Because of this type III binding mode, GSK2982772 exhibits excellent kinome selectivity–monokinase selectivity: it only inhibits RIPK1 at a concentration of 10 μM against 456 kinases. On the basis of GSK2982772 and an HTS hit, compound 95, a highly potent, orally available, and brain penetrant RIPK1 inhibitor, was discovered.(151) In both mouse and human cells, this compound strikingly suppressed necroptotic cell death. In a mouse experimental autoimmune encephalomyelitis model of MS, oral administration of compound 95 attenuated disease progression.

Figure 25

Figure 25. Chemical structures of four reported selective RIPK1 inhibitors.

Figure 26

Figure 26. Binding mode of GSK2982772 to RIPK1 (PDB 5TX5). One hydrogen bond and a bridged hydrogen bond can be observed between GSK2982772 and the Asp156 and Val76 residues. GSK2982772 has extensive hydrophobic interactions with Val31, Ile43, Lys45, Met67, Leu70, Val75, Val76, Leu78, Leu90, Met92, Leu129, Val134, and Phe162.

DNL747, a RIPK1 inhibitor whose chemical structure has not yet been disclosed, is in clinical trials by Denali Therapeutics. DNL747 is brain penetrant and was found to be safe and well tolerated in two clinical studies in patients with ALS and AD. However, a higher dose is needed for desired effectiveness, which leads to chronic toxicity. Denali Therapeutics announced a pause clinical in testing of DNL747 and planned to start clinical studies in 2021 on DNL788, an alternative compound with a superior profile.
GNE684 (96) is a potent cross-species RIPK1 inhibitor. In one study, it lessened collagen antibody-induced arthritis; moreover, this compound prevented skin inflammation triggered by mutation of Sharpin and colitis triggered by deletion of Nemo from intestinal epithelial cells.(152) Compound 97 is a potent and highly selective (monokinase selectivity) RIPK1 inhibitor with a core of dihydropyrazole. This compound displayed effectiveness in human retinitis pigmentosa and mouse models of MS.(153)
RIPK1 is a checkpoint kinase governing tumor immunity. RIPK1 inhibitors have broad applications in the field of cancer. GSK3145095, a RIPK1 inhibitor whose chemical structure is related to GSK2982772, was recently reported,(154) and currently, this compound is in phase 1 clinical trials for treatment of pancreatic adenocarcinoma, as well as other solid tumors.

3.5.2. Receptor Interacting Protein 2 Kinase

Nucleotide oligomerization domain 1 (NOD1) and NOD2 are members of the NOD-like receptor family of innate immune proteins. This pathway is implicated in many different inflammatory disorders, such as Blau syndrome, RA, inflammatory bowel disease (IBD), sarcoidosis, and asthma.(155,156) RIPK2 is a multidomain, dual specificity kinase that is ubiquitously expressed. This kinase is the convergence point for NOD1 and NOD2 signaling and has been recognized as a valid drug target for developing medical agents for a variety of autoimmune diseases.(157)
GlaxoSmithKline recently described their efforts to develop selective RIPK2 inhibitors for the purpose of treating inflammatory disorders. GSK583 (98, Figure 27) was identified and pharmacologically characterized as a highly potent 4-aminoquinoline-based RIPK2 inhibitor and a tool compound that demonstrated efficacy in inhibiting downstream NOD2 signaling in different models, including cellular models, in vivo rodent models, and ex vivo human disease models.(158) Modification of GSK583 led to the discovery of another 4-aminoquinoline-based PIPK2 inhibitor 99, which possesses higher binding affinity against PIPK2, improved PK/PD profiles, and reduced hERG ion channel activity.(159) Further optimization of 99 led to 100, which has a 4-aminoquinazoline scaffold and demonstrated good cell-based activity in human whole blood and an excellent kinase selectivity profile. However, this compound has unacceptable solubility, and thus its phosphate ester prodrug 101, with a desired pharmacokinetic profile, was developed. This prodrug exhibited effectiveness in a murine IBD disease model and in a CD and UC explant assay by blocking spontaneous cytokine release; therefore, 101 was advanced into phase 1 clinical trials in 2018.(160) Compound 102, a selective and potent RIPK2 inhibitor with a bridged bicyclic pyrazolcarboxamide scaffold, was identified through fragment-based screening and optimization. This compound will allow investigation of RIPK2 as a therapeutic target for autoinflammatory disorders.(161)

Figure 27

Figure 27. Chemical structures of six reported selective RIPK2 inhibitors.

By employing virtual library screening and a structure-based design strategy, Novartis discovered the potent selective RIPK2 inhibitor 103, which has outstanding oral bioavailability.(162) In both cellular and in vivo models, this RIPK2 inhibitor dramatically decreased proinflammatory cytokine secretion.
Cocrystallization of compound 100 with RIPK2 confirmed a type I binding mode within the ATP-binding pocket of RIPK2, as demonstrated in Figure 28 (PDB 6RNA).

Figure 28

Figure 28. Binding mode of compound 100 to RIPK2 (PDB 6RNA). Three hydrogen bonds can be observed between 100 and Ser25, Met98, and Asp164. An atypical CH···O═C hydrogen bond can be found between 100 and Met98. Additionally, 100 has extensive hydrophobic interactions with Leu24, Ala45, Lys47, Leu70, Leu79, Ile93, Tyr97, Met98, Leu153, and Ala163.

3.6. Interleukin-1 Receptor-Associated Kinase 4

As crucial sensors of innate immunity and transmembrane pattern recognition receptors, the interleukin-1 receptor family and Toll-like receptor (TLR) family recognize pathogens and initiate signaling cascades to mount immune responses. Dysregulation of TLR signaling is particularly implicated in autoinflammatory diseases, such as RA, SLE, IBD, psoriasis, and gout.
Interleukin-1 receptor-associated kinase 4 (IRAK4), a serine/threonine protein kinase, is one of the four members of the IRAK family. This kinase supports signaling from T-cell receptors and takes part in innate immune response signaling from TLRs (Figure 29). As a critical component in an animal’s response to IL-1, IRAK4 deficiency in animals led to loss of the ability to recognize bacterial and viral invaders.(163) Adults deficient in IRAK4 do not have a significant increase in the risk of serious infections. IRAK4 is critical for protective immunity against numerous pathogens in animals but is largely redundant for protective immunity in humans. Intrinsic differences between animals and humans, affecting receptors other than TLRs, may account for the observed discrepancies.(164) In view of IRAK4’s position in several signaling events, IRAK4 has been considered a critical therapeutic target for a few inflammatory diseases, such as RA, IBD, and other autoimmune diseases.(165) Combined with other robust data, it is suggested that IRAK4 inhibition has the capacity to treat lupus.(166) In the field of cancer, the IRAK4 gene may have a role in the development of prostate cancer. IRAK4 inhibitors are novel agents designed to suppress immune signaling pathways, and therefore, selective IRAK4 inhibitors have their own specific advantages for medical use, such as avoiding broad immunosuppression. To date, many IRAK4 inhibitors have been disclosed, and among them, a few are in clinical trials for autoimmune diseases and hematological malignancies.(165)

Figure 29

Figure 29. Role of IRAK4 in the MKK3/4/6-p38 and MKK4/7-JNK signaling pathways. Once ligands such as LPS and IL-1 bind to the IL-1 receptor (IL-1R) and Toll-like receptors (TLRs), respectively, IRAK4 is recruited and activated by the adaptor protein MyD88. IRAK4 then activates IRAK1-TRAF6, stimulating the NF-κB, JNK and p38 pathways. In addition, IRAK1 activates IRAK2 to regulate the expression of caspase-8. FADD, Fas-associating protein with a novel death domain; Casp-8, caspase-8.

PF-06650833 (104, Figure 30) inhibits IRAK4 with an IC50 value of 0.2 nM. Its binding mode with IRAK4 is shown in Figure 31. This highly potent IRAK4 inhibitor was identified through a fragment-based drug discovery effort.(167) It has completed a phase 2 clinical trial for RA, and new patients are being recruited for a phase 2 clinical trial for hidradentis suppurativa, a long-term skin disorder characterized by the appearance of swollen and inflamed lumps. BAY1834845 (105) and BAY1830839, developed by Bayer, are two IRAK4 inhibitors (IC50 values of 3.4 and 3 nM, respectively). BAY1834845 has completed a phase 1 clinical trial for pelvic inflammatory disease. A phase 1/2 trial study was started in patients with RA or psoriasis in 2018. BAY1830839 (structure undisclosed) has completed a single ascending dose study in healthy volunteers for RA. CA-4948 (106) is 500-fold more selective for IRAK4 than IRAK1 and simultaneously inhibits FLT3. This compound demonstrated antitumor activity in animal models, and patients are currently being recruited for phase 1 clinical trials to study its potential to treat myelodysplastic syndrome, AML, and relapsed and refractory hematologic malignancies.

Figure 30

Figure 30. Chemical structures of IRAK4 inhibitors in clinical trials (A) and recently reported (B).

Figure 31

Figure 31. Binding mode of PF-06650833 to IRAK4 (PDB 5UIU). PF-06650833 forms three hydrogen bonds with Val263, Met265, and Ser328 and two bridged hydrogen bonds with Lys213 and Ser269.

Identification of novel selective IRAK4 inhibitors remains of significant interest. For example, ND-2110 (107) and ND-2158 (108), identified by Nimbus Therapeutics, have a cyclopenta[4,5]thieno[2,3-d]pyrimidine core and are highly potent (IC50 values of 7.5 and 1.3 nM), selective, and bioavailable IRAK4 inhibitors.(168) In mouse models, these two compounds demonstrated potential efficacy in alleviating collagen-induced arthritis, suppressing LPS-induced TNF production, and blocking gout formation. These discoveries suggest that IRAK4 inhibition could be a useful therapeutic strategy in a genetically defined population of activated B-cell-like subtypes of diffuse LBCL, autoimmune disorders, and other malignancies that are dependent on aberrant MYD88 signaling. Following this, AstraZeneca developed pyrrolopyrimidine- and 5-azaquinazoline-based IRAK4 inhibitors for oral treatment of mutant MYD88L265P diffuse LBCL.(169,170)
Nicotinamide-based compound 109 is a highly selective and potent IRAK4 inhibitor (IC50 = 3.4 nM) developed by Bristol-Myers Squibb.(171) In a lipoteichoic acid-induced acute inflammation model, at a 10 mg/kg dose, this compound offered a strong PD effect with >90% inhibition. BMS-986126 (110), structurally related to 109, is a potent, highly selective IRAK4 inhibitor. Both in vitro and in vivo, BMS-986126 exhibited equivalent activity against several MYD88-dependent responses. Through modification of their previously reported dihydrobenzofuran IRAK4 inhibitors, scientists at Genentech, Inc. discovered benzolactam-selective IRAK4 inhibitors, such as 111 (IC50 = 1.4 nM). In a TLR-challenged mouse model, this IRAK4 inhibitor demonstrated strong inhibition against multiple cytokines of interest and therefore is a useful tool compound for more in vivo experiments across different disease models.(172)

3.7. Glycogen Synthase Kinase 3

As a serine/threonine protein kinase, glycogen synthase kinase 3 (GSK3) has been acknowledged as a kinase involved in many central intracellular signaling pathways, such as apoptosis, migration, glucose regulation, and cell proliferation (Figure 32).(173) GSK3 has two isoforms: GSK3α and GSK3β. In resting cells, both isoforms are constitutively active; however, they have dissimilar tissue expression. GSK3 was initially identified in the context of its participation in regulating glycogen synthase. As one of a number of signaling components downstream from the insulin receptor, GSK3 is implicated in other aspects of glucose homeostasis. In addition, GSK3 has been shown to regulate immune and migratory processes and is fundamentally involved in several pathways associated with apoptosis and cell proliferation. By relocating a phosphate moiety from ATP to a serine residue of a protein substrate, GSK3β catalyzes hyperphosphorylation of tau protein and causes the formation of toxic insoluble neurofibrillary tangles. Therefore, because GSK3 is implicated in many diseases, including cancer, type 2 diabetes, neurodegenerative and psychiatric disorders, inflammation, bipolar disorder, bone density improvement, and ALS, it has received great interest as a research subject.(174) Indeed, many chemically diverse classes of GSK3 inhibitors, including metal cations, ATP-competitive inhibitors, non-ATP-competitive inhibitors, natural products, and substrate-competitive inhibitors, have been reported and are being tested for therapeutic usage.(174) Among them, two are under clinical investigation for various disorders.

Figure 32

Figure 32. GSK3 signaling pathway. GSK3 can be activated by PI3K signaling, regulating protein synthesis and glycogen synthesis. Binding of WNT to Frizzled and LRP5/6 complex results in recruitment and activation of Dsh protein, which then inhibits a protein complex containing GSK3, AXIN, APC, CKII, and β-catenin, blocking the phosphorylation and consequent degradation of β-catenin. Once D2 receptor activation occurs, β-arrestin brings AKT and GSK3 to PP2A. PP2A dephosphorylates AKT and GSK3, deactivating AKT and activating GSK3. LRP5/6, LDL receptor-related protein 5/6; PP2A, protein phosphatase 2A.

Lithium salts are used to treat bipolar disorder, a mental disease characterized by alternating periods of elation and depression. It is believed that lithium salts are GSK3 inhibitors (IC50 = 2.0 mM) that directly bind to the protein in competition with magnesium ions.(175) Lithium carbonate was assessed in two clinical trials (NCT00790582 and NCT00818389) including ALS patients, and one revealed improved benefits, whereas the other did not find any evidence of clinical benefits.
Tideglusib (112, NP-12, or NP031112; Figure 33), developed by the Zeltia Group in Spain, has a thiadiazolidinone core. This drug is a selective, irreversible, and non-ATP-competitive GSK3β inhibitor with an IC50 value of 251 nM against GSK3β.(176) The experimental results did not suggest that tideglusib forms a covalent bond with Cys199 of GSK3β. However, the irreversible inhibition and the very low turnover rate of GSK3β are principally relevant from a pharmacological perspective of tideglusib and could have substantial implications in the therapeutic potential of GSK3β inhibitors. Tideglusib demonstrated potent anti-inflammatory and neuroprotective effects both in vitro and in vivo.(177) Tideglusib has completed a phase 2 clinical trial for AD. The results revealed that except for some moderate, asymptomatic, fully reversible increases in liver enzymes, this drug was well tolerated.(178) Unfortunately, the drug was withdrawn from AD treatment in 2012. Tideglusib completed phase 2 clinical trials for autism spectrum disorders in 2018. Currently, this drug is in clinical trials for progressive supranuclear palsy (phase 2b)(179,180) and myotonic muscular dystrophy (phase 2), and patients are beginning to be recruited for a congenital myotonic dystrophy trial, a group of genetic disorders that impair muscle functions over a long period of time. Interestingly, tideglusib provides a simple, rapid, and natural tooth repair process, which could provide a potential new approach to clinical tooth restoration.(181)

Figure 33

Figure 33. Chemical structures of GSK3 inhibitors in clinical trials.

LY2090314 (113), developed by Eli Lilly and Company, is a potent competitive GSK3 inhibitor (IC50 values of 1.5 and 0.9 nM against GSK3α and GSK3β, respectively) with limited activity against many other kinases (for example, IC50 = 79 nM against CDK5). This drug has been in clinical trials to study its ability to treat leukemia, advanced cancer, and pancreatic cancer.(182) LY2090314 contains a maleimide core, and many maleimide derivatives, including natural products, have been developed as GSK3 inhibitors.
Recently, many GSK3 inhibitors with different scaffolds have been reported. Figure 34 shows some examples. Among them, compounds 114 (GSK3, IC50 = 8 nM)(183) and CHIR-911 (115, GSK3, IC50 = 5 nM)(184) demonstrated efficacy in treatment of type 2 diabetes, and SB-216763 (116, GSK3α, IC50 = 34 nM), 117 (GSK3β/α, IC50 = 5.9/2.0 nM),(185) SAR502250 (118, GSK3, IC50 = 12 nM),(186) and PF-04802367 (119, GSK3α/β, IC50 = 10/9.0 nM)(187) were reported to have activity in lowering pTau levels in triple-transgenic AD mouse models. Compound 120 is a selective ATP-competitive GSK3β inhibitor (GSK3α/β, IC50 = 40/18 nM). In a mouse model of mania, this compound showed promising efficacy, plasma PK profile, and brain exposure, suggesting that this type of inhibitor has encouraging potential to treat mood disorders.(188) Compound 121 is a GSK3β allosteric inhibitor with an IC50 value of 2.01 nM that demonstrated promise for congenital myotonic dystrophy type 1 and spinal muscular atrophy.(189) Because of rare tridentate interactions with the GSK3 hinge region, BRD1652 (122), having a novel pyrazolo-tetrahydroquinolinone scaffold, inhibits GSK3 very potently (GSK3α/β, IC50 = 0.4/4.0 nM) and with exquisite kinome-wide selectivity. Figure 35 demonstrates the binding mode of BRD3937, an analogue of BRD1652, to human GSK3β.(190) In a dopaminergic signaling paradigm modeling mood-related disorder, this compound displayed effectiveness in vivo.

Figure 34

Figure 34. Chemical structures of several recently reported GSK3 inhibitors.

Figure 35

Figure 35. Binding mode of BRD3937 to human GSK3β (PDB 5HLP). BRD3937 forms three hydrogen bonds with residues Asp133 and Val135.

Inhibitors of GSK3 in other species, such as Plasmodium falciparum GSK3 (PfGSK3), may also have potential uses in medicine (see section 3.17). In addition, selective Trypanosoma brucei GSK3 inhibitors might be suitable as antimicrobial agents against infection by other parasites (see section 3.19).

3.8. p38α Mitogen-Activated Protein Kinase

Excessive production of TNF-α and IL-1β is thought to underlie a few inflammatory disorders. Inhibition of TNF-α function by biological agents such as TNF-α antibodies is effective in the treatment of RA and other autoimmune diseases.
p38 mitogen-activated protein kinases (p38 MAPKs) have four members, p38α, p38β, p38γ, and p38δ. p38α MAPK plays a critical role in regulating the biosynthesis of a number of inflammatory cytokines, such as TNF-α and IL-1β; thus, p38α MAPK inhibitors have been considered to be a promising solution for treatment of inflammatory diseases.(191) Indeed, preclinical studies showed that inhibition of p38α MAPK can effectively inhibit TNF-α production both in vitro and in vivo. In addition, by affecting the formation of reactive oxygen species, p38α MAPK undermines the bioavailability of nitric oxide, leading to endothelial dysfunction and vasoconstriction. Therefore, for the past two decades, the identification and development of small-molecule p38α MAPK inhibitors as orally active therapeutic agents for treatment of inflammatory diseases and cardiovascular diseases have received much interest. Many p38α MAPK inhibitors have advanced into clinical trial studies mainly for treatment of inflammatory diseases. Their structures and clinical information are listed in Table 6. Most of them are for RA; however, little success has been achieved in this field, and interest has turned to their use in other indications, such as COPD.
Table 6. Small-Molecule p38α MAPK Inhibitors Evaluated in Clinical Trials for Treatment of Nononcologic Diseasesa
a

Abbreviations used in this table: AD, Alzheimer’s disease; AS, ankylosing spondylitis; CD, Crohn’s disease; COPD, chronic obstructive pulmonary disease; RA, rheumatoid arthritis.

Although p38α MAPK was thought to be a perfect target for developing anti-inflammatory drugs, more than a dozen chemically different p38α MAPK inhibitors have not yet succeeded after long-term development. In fact, the clinical results are truly disappointing. Many of these inhibitors were found to have significant systemic side effects to various degrees, including hepatotoxicity, cardiac toxicity, and CNS disorders, which may be because p38α MAPK participates in regulation of more than 60 substrates. Additionally, within weeks, tolerance to the anti-inflammatory effect occurred. Others failed owing to unmet endpoints because of a lack of long-term efficacy. For example, in January 2016, due to an unmet primary endpoint in a phase 3a clinical trial and insufficient support for investment in phase 3b of the study, further investigation of losmapimod (124) for acute coronary syndrome was terminated. Thus, to develop feasible anti-inflammatory drugs, evaluating the potential to target upstream MAPKs, such as ASK1 (see section 3.4), is an alternative approach. Another alternative approach is to target the downstream targets of the signaling pathway, such as p38/MAPK-activated kinase 2 (MK2, see section 3.9).
The prodrug strategy has been employed for the development of p38α MAPK inhibitors. BMS-582924 (132) selectively inhibits p38α MAPK with an IC50 value of 13 nM.(192) This compound reduced TNF-α production by 78%. Because of its good pharmacokinetic profile and effectiveness in both a pseudoestablished rat AA model and an acute murine inflammation model, BMS-582924 was advanced into and finished phase 2 clinical trials to study its ability to treat RA and psoriasis-related vascular diseases. To overcome the issues of pH-dependent solubility and exposure related to this compound, BMS-751324 (139, Figure 36A) was developed, which is the clinical prodrug of BMS-582924.(193) BMS-751324 is stable and more soluble than BMS-582924 under both acidic and neutral conditions. Both of these compounds exhibited similar efficacy in a rat adjuvant arthritis model and a rat LPS-induced TNF-α model. BMS-751324 did not show pH-dependent exposure as BMS-582924 did when administered with famotidine in rats and humans. The authors claimed that this prodrug has advanced into clinical trials, but no information could be found at www.clinicaltrials.gov.

Figure 36

Figure 36. (A) Chemical structures of BMS-751324 and MW150. (B) Binding mode of MW150 to human p38α MAPK (PDB 4R3C). MW150 forms hydrophobic interactions with surrounding residues; three hydrogen bonds between MW150 and the Lys53, Met109, and Ser154 residues can be observed.

Recently, a p38α MAPK inhibitor, MW01-18-150SRM (MW150, 140), was advanced into early clinical trials for CNS disorders.(194) MW150 is a highly selective brain penetrant with appropriate pharmacodynamics and is efficacious in diverse animal models of neurologic disorders. Figure 36B shows the binding mode of MW150 to human p38α MAPK.

3.9. p38/MAPK-Activated Kinase 2

p38αMAPK inhibitors have caused significant unwanted side effects in clinical trials, which has prompted researchers to focus their attention on other downstream targets of the signaling pathway, such as p38/MAPK-activated kinase 2 (MK2). MK2 is a member of the serine–threonine kinase family and was the first identified substrate of p38 MAPK. By increasing the stability and translation of the corresponding mRNA, this kinase participates in TNF-α, IL-1β, and IL-6 synthesis and release. Under different inflammatory conditions, MK2 is activated directly by inflammatory signals and stress via p38 MAPK phosphorylation.(195) Mice with p38α MAPK knockout are afflicted with compromised fertility and embryonic lethality, whereas MK2-null mice are not influenced. Furthermore, MK2 knockout mice demonstrated considerably reduced cytokine levels in the serum and brain, along with fewer or no symptoms in lung sensitization or arthritis models. Moreover, after MK2 is depleted, neuroprotective effects are found, suggesting that chronic neuroinflammation related to neurodegenerative diseases, such as PD, AD, and MS, could in part be modulated by MK2 activity. MK2 inhibition has been demonstrated to markedly reduce the production and release of cytokines. In addition, MK2 inhibition may result in effectiveness that is similar or improved compared with p38α MAPK inhibition while avoiding the systemic toxicity exhibited by p38α MAPK inhibitors.(196) Therefore, MK2 inhibition is considered a possible alternative to p38α MAPK inhibition to treat inflammatory diseases, including RA, IBD, IPF, and asthma.(197,198) In addition, MK2 is implicated in the process of tumorigenesis; therefore, MK2 inhibitors may have potential for treatment of nonsmall cell lung cancer (NSCLC).
The crystal structure of MK2 demonstrates that the ATP-binding site is deep and narrow (Figure 37A), which allows only small planar molecules to bind. The catalytic domain of MK2 is highly homologous to that of other kinases, including MK isoforms, hampering the discovery of highly selective MK2 inhibitors. A plethora of MK2 inhibitors have been disclosed, and most are type I (ATP-competitive) inhibitors. However, no MK2 inhibitors have progressed into clinical trials because of their poor physicochemical properties, leading to insufficient oral bioavailability and permeability and mediocre cellular potency and/or efficacy in animal models.

Figure 37

Figure 37. (A) The deep and narrow ATP-binding site of MK2 (PDB 1NY3). An ADP (green ball and stick mode) is shown. (B) Binding mode of an analogue of compound 144 to MK2 (PDB 3FYJ). Two hydrogen bonds can be observed between this compound and Lys93 and Leu141. An atypical CH···O═C hydrogen bond can be found between this compound and Glu139. Additionally, this compound has extensive hydrophobic interactions with Leu70, Val78, Ala91, Lys93, Val118, Met138, Leu141, and Leu193.

Compound 141 (Figure 38), from Boehringer Ingelheim, is a potent MK2 inhibitor (IC50 = 2 nM). PF-3644022 (142, IC50 = 2 nM against MK2) demonstrated oral anti-inflammatory efficiency against both chronic and acute inflammation models in rats.(199) As an anti-TNF-α agent, compound 143 (IC50 = 54 nM against MK2) showed good in vitro cellular effectiveness, as well as in vivo efficacy in a mouse endotoxin shock mode.(200) Compound 144 inhibits MK2 with an IC50 value less than 3 nM.(201) This MK2 inhibitor was obtained by fluorinating a potent ATP-competitive MK2 inhibitor that suffered from insufficient oral bioavailability and permeability disclosed early. Compound 144 displayed improved permeability and other ADME properties, including in vivo clearance and solubility. Figure 37B shows the binding mode of an analogue of compound 144 to MK2.

Figure 38

Figure 38. Chemical structures of MK2 inhibitors discussed in the text.

Because of the high cellular concentration of ATP in cells (approximately 2–5 mM) and the high binding affinity of ATP to MK2 (IC50 = 2 μM), ATP-competitive MK2 inhibitors generally show poor biochemical efficiency. To overcome this and improve selectivity, non-ATP-competitive and uncompetitive MK2 inhibitors have been developed. Among them, compound 145 has an IC50 value of 9 nM against MK2 and an EC50 value of 0.31 μM against human TNF-α.(202) The tetracyclic compound 146 inhibits MK2 with an IC50 value of 2.9 nM and exhibited an EC50 value of 0.26 μM (inhibition of HSP27 phosphorylation in LPS-stimulated THP-1 cells).(203)

3.10. Tropomyosin Receptor Kinases

Tropomyosin receptor kinases (TRKs), belonging to the family of tyrosine kinases, include three members, TRK-A, TRK-B, and TRK-C. TRKs regulate synaptic strength and plasticity in the mammalian nervous system;(204) they are associated with neuronal survival and differentiation through several signaling pathways. Neurotrophins, a family of growth factors, are common ligands of TRKs, and their signaling plays an important role in the nervous system by regulating proliferation, cell survival, the fate of neural precursors, axon and dendrite growth and patterning. In addition, neurotrophin signaling affects the expression and activity of certain proteins, such as ion channels and neurotransmitter receptors (Figure 39). Therefore, interest in developing small-molecule TRK inhibitors, including pan-TRK and selective TRK inhibitors, to modulate neurotrophin activity is increasing. The TRK family has been considered to be a potential target class for treatment of pain.(205) In the field of oncology, TRKs are involved in malignant transformation, metastasis, chemotaxis, and survival signaling. Two TRK inhibitors, larotrectinib and entrectinib, were approved in 2018 and 2019 by the U.S. FDA to treat NSCLC and metastatic solid tumors, respectively, and a few TRK inhibitors are in clinical trials for cancer treatment. For safety issues, it is necessary that TRK inhibitors to treat cancer have minimal brain availability.

Figure 39

Figure 39. TRK signaling pathway. Neurotrophins bind to TRK receptors, leading to recruitment of adaptor proteins, including GRB2, GAB1, SHC, SHP2, FRS2, and SOS. Subsequently, Ras, PLC-γ, and PI3K are activated, triggering the MAPK pathway, calcium mobilization, and the PI3K/AKT/mTOR pathway. These signaling pathways regulate gene expression activation, neurite outgrowth, and neuronal survival associated with pain and cancer.

Because of the high conservation of the ATP-binding sites of the three members in this kinase family, the first developed TRK inhibitors have almost no selectivity among them, i.e., they are pan-TRK inhibitors. Among them, PF-06273340 (147, Figure 40) is currently in clinical trials for pain treatment. As a potent, selective pan-TRK inhibitor inhibiting TRK-A, TRK-B, and TRK-C with IC50 values of 6, 4, and 3 nM, respectively, PF-06273340 is efficacious, peripherally restricted, and well tolerated.(206) PF-06273340 binds to the DFG-out form of TRK (see Figure 41A). This drug progressed into phase 1 clinical trials for development as a pain killer. In healthy human subjects, a randomized, single-dose, double-blind, placebo- and active-controlled five-period crossover study was carried out (NCT02260947) on this drug.(207)

Figure 40

Figure 40. Chemical structures of several reported TRK inhibitors.

Figure 41

Figure 41. (A) Binding mode of PF-06273340 (PDB 5JFX) to TRK-A. PF-06273340 forms three hydrogen bonds with the Met592 and Asp668 residues and two bridged hydrogen bonds with the Arg574 and Glu590 residues. (B) Binding mode of compound 152 (PDB 6D20) in an allosteric pocket of TRK-A. Compound 152 forms four hydrogen bonds with Leu486, Asp668, and Arg673. An NH+–π interaction can be observed. For comparison, PF-06273340 is shown as a green wire model.

CE-245677 (148), identified as an oral pan-TRK/Tie2 inhibitor by Pfizer, has been treated as a potential treatment for certain cancer types; however, identified CNS side effects led to termination of phase 1 multiple-dose trials.(208) This compound demonstrated both efficacy in multiple pain models and CNS side effects. Compound 149 inhibits TRK-A, TRK-B, and TRK-C with IC50 values of 8.4, 6.2, and 2.2 nM, respectively, and exhibits outstanding TRK selectivity against 44 kinases.(209) Compound 149 was predicted to exhibit low metabolic clearance in humans, hence avoiding the potential clearance prediction liability related to PF-06273340. Compound 149, along with two analogues, was regarded as an exciting and promising structurally differentiated asset suitable for advancement into a variety of clinical pain studies. Scientists at Merck reported their efforts to develop a series of several small-molecule selective pan-TRK inhibitors from hits obtained by HTS.(210) Compound 150 exhibited excellent cellular potency and an extended residence time on the enzyme and was chosen for investigation in an inflammatory model and a neuropathic pain model. Compound 151 is a pan-TRK inhibitor with excellent selectivity against other kinases and was designed from the aurora A kinase inhibitor tozasertib, a drug in clinical phase 2 trials for cancer treatment.(211) Compound 151 may serve as an advanced hit compound for treatment of acute and chronic pain or other conditions resulting from abnormal TRK-A activity, such as inflammation and cancer.
TRK-A, also named high affinity nerve growth factor receptor, causes cell differentiation and may be involved in specifying sensory neuron subtypes. Nerve growth factor (NGF) binds to TRK-A, and blockade of the TRK-A signaling pathway by the NGF antibody tanezumab has been clinically validated for pain treatment, which provides clinical proof of concept for the benefit of TRK-A pathway inhibition in pain. This result provides researchers with great motivation for the development of small-molecule selective TRK-A inhibitors to treat chronic pain. For this purpose, adequate TRK-A selectivity over TRK-B and TRK-C is desirable. However, there are no residue differences in the ATP-binding sites among TRK-A, TRK-B, and TRK-C, signifying that it is very challenging to develop selective TRK-A inhibitors that bind to this site. Allosteric TRK-A inhibitors may have improved isoform selectivity. Indeed, compound 152 binds TRK-A in an allosteric pocket located behind the ATP-binding site with an IC50 value of 10 nM (Figure 41B) and demonstrated high selectivity over TRK-B/C and the kinome.(212) This compound was efficacious in preclinical pain models and demonstrated good oral absorption combined with extensive peripheral restriction and a clean in vivo toxicity profile.
AR786, whose chemical structure is not disclosed, is a selective TRK-A inhibitor that binds to an allosteric site. AR786 has IC50 values of 0.6 nM and >1000 nM against human TRK-A and TRK-B in cells and has high off-target kinase selectivity. This compound demonstrated good oral exposure in rodents and maintained high peripheral distribution relative to the CNS. In a rodent model of peripheral pain, inhibition of the TRK-A receptor via allosteric modulation was sufficient to demonstrate significant and sustained relief of nociceptive pain. For pan-TRK inhibitors, such as AR470 or AR772 (structures unknown), there were no observed benefits of simultaneously inhibiting the brain-derived neurotrophic factor/TRK-B axis. AR786 was shown to have similar efficacy in monoiodoacetate and medial meniscal transection models of osteoarthritis pain. AR786 reduced the paw withdrawal threshold and weight bearing asymmetry in both models at a dose of 30 mg/kg (PO, BID) in comparison with sham controls. Although it does not affect joint pathology, AR786 attenuates monoiodoacetate-induced synovitis.(213) AR786 was first developed by Array BioPharma Inc., and in 2016 was codeveloped in collaboration with Asahi Kasei Pharma as a selective TRK-A inhibitor for pain and inflammation.
Brain-derived neurotrophic factor, which binds to TRK-B, might be useful as a therapeutic agent for a variety of neurological disorders. Inhibition of TRK-B may lead to an antidepressant effect. Compound 153, a dihydroxyflavone analogue, is a selective TRK-B agonist that has robust TRK-B activation in the hippocampus of the mouse brain, whereas TRK-A is not activated.(214) Chronic oral administration of this compound markedly reduced immobility in two classical antidepressant behavioral animal models (tail suspension test and forced swim test). Compound 153 has the potential to be a candidate for in-depth drug development for treatment of various neurological diseases, such as depression. 7,8-Dihydroxyflavone (compound 154,7,8-DHF), another potent and selective TRK-B agonist mimicking the effect of brain-derived neurotrophic factor, improved motor function and reduced motoneuron loss in SOD1G93A ALS model mice.(215)

3.11. c-Jun-N-Terminal Kinases

As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis, immune response, and autophagy when they are activated by various stimulating factors, including growth factors, cytokines, neurotoxins, oxidative stress, and fatty acids. To date, there are three human JNK genes, jnk1, jnk2 and jnk3, which encode 10 diverse splice JNK variants (four JNK1/2 isoforms and two JNK3 isoforms). JNK1/2 are widely expressed; nevertheless, JNK3 is explicitly expressed in the brain at high levels and in the heart and testis at low levels.(216)
JNK1/2 has been shown to have an important role in autoimmune disorders, such as RA, IBD, endometriosis, and psoriasis. Studies have shown that the release of proinflammatory cytokines, such as TNF-α and IL-1β, is triggered by the JNK pathway.(217) Inhibition of JNKs decreased LPS-induced TNF-α release, reduced immune cell proliferation in multiple sclerosis, and showed anti-inflammatory effects in collagen-induced arthritis.(218)
Among the JNKs, JNK3 has been considered an attractive therapeutic target for CNS disorders, such as AD and PD. JNK3 promotes formation of the amyloid-β (Aβ) product by phosphorylating the Aβ precursor protein.(219) Furthermore, JNK3 is expressed in the Tau protein, affecting the stability of the cytoskeleton.(220) JNK3 also directly phosphorylates Tau protein, regulating the formation of neurofibrillary tangles, which is positively correlated with cognitive impairment and neuron loss. Knockout or inhibition of JNK3 in mice led to amelioration of neurodegeneration in animal models. In addition to the inflammatory and CNS diseases discussed above, JNKs have been considered potential drug targets for cancer, metabolic disorders, fibrosis, and cardiovascular diseases due to their potential pathological functions in vivo.
SP600125 (155, Figure 42) is the first reported potent pan-JNK inhibitor (JNK1, IC50 = 40 nM; JNK2, IC50 = 40 nM; JNK3, IC50 = 90 nM) with poor selectivity over other MAPKs, such as p38 MAPKs and extracellular signal-regulated kinases. SP600125 was used for treatment of various conditions with the aim of exploring the specific roles of JNKs in different diseases. Studies have indicated that SP600125 leads to decreased formation of neurofibrillary tangles and senile plaques and improves AD-associated cognitive deficits in homozygous APPswe/PS 1dE9 double-transgenic mice.(221) In addition, SP600125 showed efficacy in a number of animal models of fibrosis.(222)

Figure 42

Figure 42. Chemical structures of representative JNK inhibitors for treatment of nononcologic diseases.

AS-602801 (156) is another pan-JNK inhibitor (JNK1, IC50 = 80 nM; JNK2, IC50 = 90 nM; JNK3, IC50 = 230 nM) that was identified in the process of drug development for neurological diseases. In 2012, this compound reached phase 2 clinical trial studies to evaluate its ability to treat inflammatory endometriosis,(223) a disorder associated with the presence of endometrial tissue outside the uterine cavity, sensory nerve recruitment, inflammation, and T-cell involvement.
Tanzisertib (157, CC-930), a potent pan-JNK inhibitor (JNK1, IC50 = 61 nM; JNK2, IC50 = 7 nM; JNK3 IC50 = 6 nM) developed by Celgene, was investigated for treatment of discoid lupus erythematosus and IPF in clinical trials in 2011. However, the investigation was discontinued in phase 2 clinical trials for undisclosed reasons.(224)
XG-102, a bidentate peptide JNK inhibitor, targets the JNK-interacting protein binding site to block the interaction of JNK with certain substrates, such as ATF2, c-Jun, and ELK1. It was found that XG-102 potently blocks p38α MAPK signaling and exhibits a synergistic effect with JNK pathway inhibition.(225) A phase 3 clinical trial was completed in patients with acute sensorineural hearing loss in 2016, and phase 3 trials for treatment of postcataract surgery intraocular inflammation were started in 2015. Its derivative XG-104 (JNK1, IC50 = 722 nM; JNK2, IC50 = 155 nM; JNK3, IC50 = 1102 nM) entered phase 2 for dry eye syndrome treatment in 2014.
In addition to pan-JNK inhibitors, development of selective JNK3 inhibitors for CNS treatment has received broad interest in recent years. Compound 158 is a selective JNK3 inhibitor with an IC50 value of 40 nM against JNK3 and showed 2500-fold selectivity over JNK1α1 and JNK2α2 isoforms and excellent kinome selectivity over 398 kinases.(226)In vivo studies showed that compound 158 significantly reduced spatial memory impairment by lowering Aβ accumulation and Tau phosphorylation. Additionally, it exhibited neuroprotective activity in vitro. Compound 159 is a novel selective JNK3 inhibitor with an IC50 value of less than 1 nM against JNK3, 200-fold selectivity over JNK2, 500-fold selectivity over JNK1, and 20 000-fold selectivity over p38α MAPK.(227) However, this compound and its analogues showed poor pharmacokinetic properties in oral dosing; thus, future optimization will require improvement of oral pharmacokinetic properties if oral administration is preferred.

3.12. Leucine-Rich Repeat Kinase 2

As a member of the ROCO protein family, leucine-rich repeat kinase 2 (LRRK2, also known as RIPK7) is a very large multidomain serine–threonine kinase that includes a kinase domain and a GTPase domain.(228) It is comprised of 2527 amino acids and is expressed in many tissues, especially throughout the brain, including the striatum, olfactory bulb, hippocampus, cortex, brainstem, midbrain, and cerebellum. LRRK2 participates in many biological pathways. Mutations in LRRK2, such as G2019S, are related to an increased risk of PD; therefore, LRRK2 is genetically linked to PD.(229) It has been hypothesized that LRRK2 inhibition may be a potential way to alter PD pathogenesis. In addition, LRRK2 is associated with CD, leprosy, and some cancer types; therefore, this kinase target has received great interest for the development of potent brain penetrant inhibitors, and many LRRK2 inhibitors have been reported.(230,231) Potent and selective LRRK2 inhibitors may function as key tools to understand LRRK2 mechanisms and may offer additional insights into the roles of LRRK2 in PD pathogenesis.
The design of LRRK2 inhibitors has been hindered in part by the complexity of this large multidomain kinase, which has not yet been crystallized. However, different potent, brain permeable, selective LRRK2 inhibitors have recently been reported. Figure 43 shows a few well-known LRRK2 inhibitors, including GSK2578215A (160),(232) GNE-7915 (161), GNE-0877 (162),(233) PF-06447475 (163),(234) and compounds 164(235) and 165.(236) Nevertheless, a few preclinical studies have demonstrated that LRRK2 inhibition may lead to potential side effects in peripheral tissues, such as the lung and kidney. However, studies of two LRRK2 inhibitors (GNE-7915 and GNE-0877) confirmed the potential problems induced by inhibition of LRRK2.(237) These assessments of toxicity in rodents demonstrated that these two LRRK2 inhibitors do not cause lung or kidney changes. In primates, normal kidney function was found, but some toxicity issues did exist in the lungs. In two mouse models of LRRK2-associated PD, GNE-7915 enhanced dopamine release and improved cell function; thus, it was concluded that GNE-7915 should be effective for treatment of PD.(238)

Figure 43

Figure 43. Chemical structures of representative selective LRRK2 inhibitors.

To date, two LRRK2 inhibitors, DNL-201 (likely to be GNE-7915) and DNL-151 from Denali Therapeutics, have been in phase 1 clinical trials for PD treatment. In healthy volunteers, the phase 1a study of these two drugs showed good tolerability and inhibition of peripheral LRRK2 kinase activity. After completing their phase 1 clinical trials, Denali Therapeutics decided to initiate testing of one of the two LRRK2 inhibitors in a phase 1b study, enrolling patients with LRRK2-associated PD to further evaluate safety as well as biomarkers.

3.13. Ketohexokinase

In recent decades, the utilization of fructose, or fruit sugar, as a common food additive and sweetener has increased and has been associated with metabolic disorders, including nonalcoholic fatty liver disease, steatohepatitis, insulin resistance, and cardiovascular disease. Ketohexokinase (KHK, also known as hepatic fructokinase) catalyzes the phosphorylation of fructose to produce fructose-1-phosphate, which initiates the metabolic cascade of fructose.(239) KHK has two isoforms, KHK-A and KHK-C. The latter is the primary enzyme for fructose metabolism because it has a lower KM and a higher Vmax than KHK-A. Fructose is primarily metabolized in turn by the intestines, liver, pancreas and kidney, all of which express KHK-C. Therefore, KHK has been regarded as a promising therapeutic target for the development of medical agents to treat nonalcoholic fatty liver disease. hyperlipidemia, insulin resistance, and obesity.
A few KHK inhibitors have been reported. Compound 166 (Figure 44), a KHK inhibitor with an IC50 value of 330 nM, was identified through a fragment-based drug design paradigm.(240) Compound 167 was identified as a KHK inhibitor (IC50 values of 0.45 and 0.39 μM against hKHK-C and hKHK-A, respectively) with minimal off-target activity through a combination of structure-based drug design, fragment-based screening, and parallel medicinal chemistry.(241) This compound has several positive attributes of a lead. In vivo pharmacology studies showed that 167 induced a dose-dependent decrease in fructose-1-phosphate formation in the liver and kidney with concomitant increases in plasma fructose concentrations. PF-06835919 (168), built upon compound 167, is a highly potent KHK inhibitor (IC50 value of 10 nM) with a core of 3-azabicyclo[3.1.0]hexane acetic acid. It is interesting to note that after modification of the (S)-3-methylpyrrolidin-3-ol moiety of compound 167, the obtained KHK inhibitors, for example, PF-06835919, may have a different rotated binding mode, as demonstrated in Figure 45. In this binding mode, the carboxylate group of PF-06835919 has three hydrogen bonding interactions with the cationic guanidinium group of Arg108 and the backbone NHs of Ala256 and Gly257; another hydrogen bond bridged by a bound water molecule between the pyrimidine ring and the carbonyl group of Cys282 can be observed; and the trifluoromethyl group fills the hydrophobic pocket defined by the Ala244, Pro246, and Pro247 residues.

Figure 44

Figure 44. Chemical structures of three reported KHK inhibitors.

Figure 45

Figure 45. Binding mode of PF-06835919 to KHK (PDB 6W0Z). Three hydrogen bonds with Arg108, Ala256, and Gly257 and a bridged hydrogen bond with Cys282 can be observed between PF-06835919 and KHK.

The in vivo pharmacokinetic properties of PF-06835919 were determined in rats and dogs, and in both species, this KHK inhibitor demonstrated a moderate to long elimination half-life, negligible renal excretion as an unchanged parent and high oral bioavailability. The observed dose-dependent decrease in hepatic and kidney fructose-1-phosphate indicates inhibition of liver and kidney KHK. Representing a first-in-class small-molecule KHK inhibitor, PF-06835919 has entered phase 2 clinical trials for treatment of nonalcoholic fatty liver disease and steatohepatitis.

3.14. G Protein-Coupled Receptor Kinase 2

Belonging to the AGC family, G protein-coupled receptor kinases (GRKs) canphosphorylate activated G protein-coupled receptors and thereby initiate their uncoupling from heterotrimeric G proteins and their internalization. GRKs have seven isoforms and are divided into three subfamilies: GRK1 (including GRK1 and 7), GRK2 (including GRK2 and 3), and GRK4 (including GRK4–6). GRK2, also named β-adrenergic receptor kinase 1 (βAR-kinase 1), phosphorylates agonist-occupied βAR and promotes arrestin-mediated binding of βAR to the Gβγ subunit of the G-protein and βAR-G protein uncoupling, further leading to βAR desensitization and downregulation (Figure 46).(242) Increased βAR desensitization and downregulation are correlated with chronic heart failure, which may lead to death. In addition, upregulation of GRK2 influences cardiac glucose uptake, leading to abnormal cardiac metabolism and affecting new cardiomyocyte growth.(243) Studies have shown that GRK2 inhibition by overexpressed βARKct, a peptide GRK2 inhibitor from a portion of the c-terminus of GRK2, or cardiac-specific GRK2 gene ablation leads to increases in βAR density and βAR responses and improved cardiac function and survival in several heart failure models.(244,245)

Figure 46

Figure 46. GRK2 signaling pathway. In the adrenal medulla and cardiac sympathetic nerve terminal, upregulation of GRK2 leads to α2 adrenergic receptor (α2AR) dysfunction, causing a massive release of catecholamines (norepinephrine and epinephrine). Catecholamines in turn stimulate the βARs present on cardiomyocytes, activating AKT and GRK2. GRK2 blocks sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) signaling, which is involved in regulation of the contractile response and cardiac hypertrophy. In addition, GRK2 phosphorylates insulin receptor substrate-1 (IRS1), blocking glucose transporter type 4 (GLUT4) translocation from the cytosol to the plasma membrane. GRK2 also regulates β-oxidation rates and increases activation of the mitochondrial permeability transition pore (MPTP), which is associated with cellular death.

Paroxetine (169, Figure 47), a serotonin reuptake inhibitor, has been approved by the FDA. It has been used for treatment of depression, anxiety, obsessive–compulsive disorder, and posttraumatic stress disorders. It also has modest potency against GRK2, with an IC50 value of 1.1 μM (at 5 μM ATP) and >6-fold selectivity for GRK2 over other GRKs. Paroxetine was shown to improve left ventricular activity and decrease cardiac remodeling in a mouse model of myocardial infarction by inhibiting GRK2.(246) Optimized from paroxetine, GSK180736A (170), with an IC50 value of 0.77 μM against GRK2, demonstrated >100-fold selectivity against other GRKs. However, it lacks selectivity over ROCK1 and shows poor bioavailability.(247)

Figure 47

Figure 47. Chemical structures of representative GRK2 inhibitors discussed in the text.

The natural product balanol (171) is a pan-GRK inhibitor that inhibits GRK2 with an IC50 value of 50 nM (at 3 μM ATP) but also potently inhibits GRK1 and GRK3–7 (GRK1, IC50 = 340 nM; GRK3, IC50 = 47 nM; GRK4, IC50 = 260 nM; GRK5, IC50 = 160 nM; GRK6, IC50 = 490 nM; and GRK7, IC50 = 180 nM). In addition, it inhibits AGC.(248) As a derivative of balanol, Takeda103A (172), developed by Takeda Pharmaceuticals, displayed improved activity and selectivity, with an IC50 value of 20 nM (at 5 μM ATP) against GRK2 and was 50-fold more potent against GRK2 than against other tested AGC kinases. However, Takeda103A failed to enter clinical trials because of poor pharmacokinetic properties.(249) Combining the pharmacophore of GSK180736A with Takeda103A, CCG-224406 (173) was identified as a GRK2 inhibitor with an IC50 value of 130 nM that showed >700-fold selectivity over other GRK subfamilies and ROCK1. CCG-224406 showed significant cardiomyocyte potency in mouse cardiomyocytes in vitro.(250)
The novel selective GRK2 inhibitor 174 (IC50 = 18 nM) was designed from a hydrazone derivative and a 1,2,4-triazole derivative that were hit compounds identified by HTS.(251) Compound 174 showed good selectivity against GRK1, 5, 6, and 7, protein kinase C (PKC), and ROCK (GRK1, IC50 = 3100 nM; GRK5, IC50 = 2300 nM; GRK6, IC50 > 30000 nM; GRK7, IC50 > 25000 nM; PKC, IC50 = 8100 nM; ROCK, IC50 = 1400 nM) but exhibited almost comparable inhibitory activity against GRK3 (GRK3, IC50 = 5.4 nM). Compound 174 potentiated βAR-mediated cAMP accumulation and arrested internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol, suggesting that it could be a potential candidate for heart failure treatment. However, currently, no GRK2 inhibitors are in clinical trials or have been approved.

3.15. NF-κB Inducing Kinase

As a family of transcription factors, NF-κB controls DNA transcription, cytokine generation, and cell survival. NF-κB exists in almost all animal cell types and is involved in cellular responses to stimuli and the immune response to infection. NF-κB signaling occurs through two distinct canonical and noncanonical pathways.(252) NF-κB inducing kinase (NIK, also known as mitogen-activated protein kinase kinase kinase 14, MAP3K14) is a serine/threonine protein kinase. As a critical kinase in the alternative NF-κB activation pathway, NIK binds to TNF receptor-associated factor 2 and stimulates NF-κB activity. It mediates noncanonical NF-κB signaling downstream of multiple TNF family members. Augmented NF-κB activities are related to inflammatory diseases, autoimmune diseases, and cancer and are correlated with abnormal stabilization and activation of NIK. Therefore, NIK has been assumed to be an attractive drug target to develop therapeutic agents for treatment of SLE, inflammatory diseases, and cancer, among others. However, although NIK inhibitors have great potential, only a few NIK inhibitors have been reported, and no NIK inhibitors have advanced into clinical trials.
Compound 175 (Figure 48), containing an alkynol fragment, was developed by Amgen. This compound has excellent NIK inhibitory potency (Ki = 0.4 nM). It was confirmed that 175 protects the liver from oxidative stress, inflammation induced by toxin, and injury.(253) To improve the potency and selectivity of a series of NIK inhibitors with a benzoxepine core over PI3Kδ, structure-based drug design was employed, and the selective and potent NIK inhibitor 176 was obtained. This NIK inhibitor cleanly inhibits the noncanonical over the canonical NF-κB pathway in HeLa cells.(254)

Figure 48

Figure 48. Chemical structures of six NIK inhibitors discussed in the text.

Compound 177 was identified as a highly potent and selective NIK inhibitor (Ki = 0.17 nM) through a structure-guided scaffold-hopping campaign.(255)Figure 49 shows its binding mode to murine NIK (PDB 6G4Z). Two hydrogen bonds are formed between this compound and the hinge region of NIK, and the alkyne motif of compound 177 traverses a narrow channel, allowing access to a small pocket wherein 177 makes two hydrogen bonds and hydrophobic interactions that drive both NIK potency and broad kinome selectivity. SMI1 (178), an analogue of 177, can treat experimental lupus in NZB/W F1 mice and led to improved survival, lower proteinuria scores, and reduced renal pathology, demonstrating that NIK inhibition is a potential strategy for SLE treatment.(256)

Figure 49

Figure 49. Binding mode of compound 177 to murine NIK (PEB 6G4Z). Compound 177 forms hydrophobic interactions with surrounding residues, and four hydrogen bonds between this compound and residues Glu442, Glu472, Leu474, and Asp536 can be observed.

Compound 179, obtained through structure-based drug design, is a highly selective NIK inhibitor (IC50 = 9.87 nM). This compound demonstrated selective inhibitory activity toward LTβR-dependent p52 translocation and NF-κB2-related gene transcription.(257) In an imiquimod-induced psoriasis mouse model, oral administration of different doses of compound 179 showed effective antipsoriasis activity with alleviation of invasive erythema, swelling, skin thickening, and scales. Compound 180 (IC50 = 9.1 nM against NIK) is orally bioavailable in mice and efficiently suppresses the expression of NIK-induced liver inflammation-related genes in isogenic primary hepatocytes, indicating the therapeutic potential of NIK inhibitors for treatment of liver inflammatory diseases.(258)

3.16. Polo-like Kinase 2

The family of Polo-like kinases (PLKs) has five members, PLK1–5. All of them are highly conserved serine–threonine kinases that participate in the mammalian cell cycle and are involved in cell growth and checkpoint regulation of mitosis in various species. Among these five members, PLK1, having pivotal roles in mitosis, has significant clinical relevance and has been considered a bona fide target for the development of anticancer drugs.(259) Several PLK1 inhibitors, including BI 2536, onvansertib, and BI 6727 (volasertib), have entered into clinical trials for cancer treatment and have shown promising anticancer effects.(260) However, whether PLK1 is an oncogene is under debate because data have shown that PLK1 can sometimes act as a tumor suppressor.(261)
Both PLK2 and PLK3 are acidophilic kinases; however, our present knowledge of their biological roles is limited and fragmentary.(262) PLK2 and PLK3 are highly homologous to PLK1 and have been documented as tumor suppressor genes, but recent studies have shown that PLK2 is an independent prognostic marker and regulates tumor growth and apoptosis via the Fbxw7/cyclin E pathway in colorectal cancer and that PLK2 acts as a promoter in human tumor cells.(263) PLK2 is expressed in several cancer cell lines, and selective PLK2 inhibitors exhibit antitumor activity in the nanomolar range against different cancer cell lines.(264)
α-Synuclein is the major component of Lewy bodies, and PLK2 phosphorylates α-synuclein at serine 129, suggesting that PLK2 may play a key role in the progression of Parkinson’s-like pathologies.(265) PLK2 regulates α-synuclein levels through a transcription-based mechanism, which is active in cells and brain tissue. Inhibition of PLK2 may provide an alternative strategy for modulating α-synuclein levels and thereby for altering disease progression in synucleinopathies.(265) Therefore, PLK2 may serve as a potential therapeutic target for PD and related Lewy body diseases. To examine this hypothesis, Elan Pharmaceuticals designed and synthesized selective PLK2 inhibitors with potency in the nanomolar range.(266) These PLK2 inhibitors, such as ELN 582175 (181), ELN 582646 (182), and compound 183 (Figure 50), are highly selective, orally active, and brain permeable. ELN 582175 significantly reduced the level of phosphorylated α-synuclein in the rat brain after oral administration and has been considered a useful probe for future studies of PD.(267)

Figure 50

Figure 50. Chemical structures of a few reported selective PLK2 inhibitors.

Our group also developed selective PLK2 inhibitors (for example, compounds 184 and 185) using the selective PLK1 inhibitor BI 2536 as the starting point.(264) BI 2536, an ATP-competitive inhibitor, is a dihydropteridinone derivative exhibiting nanomolar potency against PLK1.(268) This compound exhibited significant anticancer activity and was well tolerated in the first clinical trials in patients with refractory or relapsed AML and advanced solid tumors. However, further development of BI 2536 was terminated by Boehringer Ingelheim.

3.17. Plasmodial Kinases

The emergence of resistance to current antimalarial drugs, including artemisinin, demands novel therapeutic strategies to treat malaria. Five Plasmodium species cause human malaria. Among them, Plasmodium falciparum (P. falciparum) is the most virulent species of human malaria and was responsible for 50% of all malaria cases and 91% of the 446 000 malaria-related deaths worldwide in 2016. P. falciparum provides many protein kinases and a small set of lipid kinases involved in critical signaling pathways at different stages of the parasite life cycle to develop next-generation antimalarials. Plasmodial kinases offer a possible advantage in that high selectivity over human kinases can be achieved.(269) This section summarizes several plasmodial kinases that have been targeted to develop antiplasmodial agents, and many potent inhibitors of these kinases have been reported. Currently, among the many disclosed inhibitors targeting plasmodial kinases, MMV048 (186, previously MMV390048, Figure 51), a P. falciparum phosphatidylinositol 4-kinase (PfPI4K) inhibitor, has progressed to human clinical trials to treat malaria.

Figure 51

Figure 51. Chemical structures of inhibitors of plasmodial kinases discussed in the text.

3.17.1. PfPI3K and PfPI4K

PfPI3K and PfPI4K, two lipid kinases, are essential survival phosphoinositide lipid kinases (PIKs) of the parasite and are considered promising targets to treat malaria.(270) To date, the discovery of PfPI3K inhibitors is still in its infancy, and very few PfPI3K inhibitors have been reported. However, a well-known antimalarial, dihydroartemisinin (187), was shown to inhibit PfPI3K with an IC50 value of 4.1 nM.(271)
PfPI4K, operating in all life-cycle stages of the parasite, is a novel drug target for the development of next-generation antimalarial drugs to cure, prevent, and block transmission of the disease. Many PfPI4K inhibitors have been reported.(270) Among them, MMV048 (186), with a core of 2-aminopyridine, demonstrated high antiplasmodial activity against K1 (chloroquine and drug-resistant strain, IC50 = 0.025 μM) and NF54 (chloroquine-susceptible strain, IC50 = 0.028 μM) and was superior to chloroquine against the K1 strain. This compound can block all life cycle stages of the malaria parasite and has favorable ADMET and PK properties.(272) MMV048 completely cured P. berghei-infected mice with a single oral dose of 30 mg/kg. At present, this drug is in phase 2a in Ethiopia for malaria treatment.
A cell-based screen against P. falciparum asexual blood-stage parasites identified a new class of antimalarials with an imidazopyrazine scaffold (see the typical compound KAI715, compound 188).(270) Such compounds are active against several drug-resistant strains, with IC50 values of 27–70 nM. In rodent malaria models, they displayed potent therapeutic, preventive, and transmission-blocking activities. These compounds were active against blood-stage field isolates of the major human pathogens P. falciparum and Plasmodium vivax and inhibited liver-stage hypnozoites in the simian parasite Plasmodium cynomolgi. Forward genetics was used to elucidate their targets, and the experimental data, including convincing chemical and genetic evidence, confirmed that PI4K is the direct target.

3.17.2. PfGSK3

PfGSK3 was demonstrated to be an important enzyme for completion of the asexual erythrocytic cycle of the parasite and consequently was suggested as a putative antimalarial drug target.(273) Compound 189 inhibits PfGSK3 with an IC50 value of 0.48 μM and is selective over the mammalian GSK3 orthologue.(274)

3.17.3. P. falciparum Cyclin-Dependent-like Kinase (PfCLK3)

PfCLK3, which is involved in multiple parasite life stages, has recently been validated as an effective target.(275)PfCLK3 is the key regulator of RNA processing and maintains the asexual blood stage of both P. falciparum and P. berghei. Inhibition of PfCLK3 by SMKIs would be an effective strategy to kill the parasite at all stages of the life cycle, including the blood, liver, and sexual stages, in which RNA splicing is required. A probe molecule, TCMDC-135051 (190), was identified as a PfCLK3 inhibitor that kills blood-stage P. falciparum. This compound has parasiticidal activity and led to a decrease in more than 400 gene transcripts essential for parasite survival by inhibiting PfCLK3. Because of the homology between CLK3 orthologues in other Plasmodium species, TCMDC-135051 showed potent inhibitory activity against CLK3 from P. vivax and P. berghei and killed the blood stages of P. berghei and Plasmodium knowlesi. In addition, PfCLK3 inhibition kills liver-stage P. berghei parasites and prevents P. berghei infection in mice; furthermore, by blocking infection of mosquitoes, this kinase prevents the development of P. falciparum gametocytes. TCMDC-135051 showed selectivity for PfCLK3 compared with the closely related human kinase CLK2, the human orthologues of PfCLK3, and PfCLK1 and other parasite kinases.

3.17.4. P. falciparum Calcium-Dependent Protein Kinases (PfCDPKs)

In Plasmodia, CDPKs are the main calcium signaling transducers. PfCDPK1, which is highly expressed in the asexual blood and mosquito stages, is associated with parasite motility, host invasion by P. falciparum, microneme secretion, and gametogenesis and is an interesting target for blocking transmission. Many PfCDPK1 inhibitors have been reported, but most of them lose the connection between enzyme potency and antiplasmodial activity. Compound 191 (IC50 = 12 nM against PfCDPK1) demonstrated significant efficacy in a P. berghei mouse infection model.(276)PfCDPK4 is vital for exflaggelation and sporozoite invasion of hepatocytes. Although unimportant for blood stage parasite proliferation, inhibitors of PfCDPK4 would be valuable as part of an extended gametocyte transmission blocking regimen. BKI-1 (192) inhibits PfCDPK4 with an IC50 value of 4 nM and blocks exflaggelation in P. falciparum with an EC50 value of 35 nM.(277)

3.17.5. P. falciparum cGMP-Dependent Protein Kinase (PfPKG)

PfPKG targets at least 69 proteins and influences several cellular activities in Plasmodia at various stages of the life cycle. PfPKG is essential for blood stage replication in the human host. Inhibition of PfPKG results in blockade of egress from mature schizonts. Compound 193 inhibits PfPKG very potently (IC50 = 0.16 nM) and selectively, displays significant potency over the asexual blood stage of P. falciparum, and blocks gametocyte transmission to Anopheles mosquitoes.(278)

3.17.6. P. falciparum MO15-Related Kinase (PfMRK)

PfMRK belongs to the CDK family and plays a critical role in DNA replication and transcriptional control. On the basis of the structural differences within the ATP-binding pockets between PfMRK and CDK7 (mammalian homologue of PfMRK), many specific PfMRK inhibitors have been identified. Among them, compound 194, a flavonoid natural product, inhibits PfMRK with an IC50 of 40 nM and demonstrated antiplasmodial activity.(269)

3.18. Toxoplasma gondii Calcium Dependent Protein Kinase 1

As a widespread parasite, Toxoplasma gondii (T. gondii) infects all warm-blooded animals (including humans) and is transmitted through food (undercooked meat or oocyst-contaminated food) and water.(279) Its tachyzoites disseminate to all organs and readily form tissue cysts within endothelial cells in the lung or retina and neurons in the brain. Most T. gondii infections in humans can be well controlled by immune responses, resulting in mild illness. However, because tachyzoites reemerge and proliferate rapidly, immunocompromised patients may suffer from toxoplasmosis, an infectious disease with serious risks, including toxoplasmic encephalitis, pneumonia, and retinitis. In addition, toxoplasmosis can cause much harm to immunocompromised organ transplant and cancer chemotherapy patients.
Currently, inhibition of the folate pathway, for example, with the dihydrofolate reductase blocker pyrimethamine and the folate antagonist sulfadiazine, is being tested for toxoplasmosis treatment in clinical trials. However, these drugs exhibit several side effects, including allergic reactions to the sulfonamide drug and bone marrow suppression due to the pyrimethamine drug. In addition, although effective against acute infection, this therapy is unable to cure chronic infection.
T. gondii calcium-dependent protein kinase 1 (TgCDPK1) is a crucial kinase for the intracellular phases of T. gondii infection, controlling microneme secretion. It has an essential role in parasite motility, cell invasion, and egress. Inhibition of TgCDPK1 has been a potential strategy for toxoplasmosis treatment. Genetic or pharmacological deficiency of TgCDPK1 displayed antiparasitic efficacy in vitro and reduced established T. gondii infection in mice.(280) Moreover, TgCDPK1 possesses a special Gly gatekeeper in its ATP-binding pocket, which is entirely unprecedented in human kinases.(281) This unusual feature indicates that TgCDPK1 could be an effective and safe target for the development of antiparasitic drugs.
A series of pyrazolopyrimidine-containing TgCDPK1 inhibitors derived from ATP were identified.(282,283) To enhance selectivity and potency, a large hydrophobic substituent at the C-3 position of the pyrazolo-pyrimidine scaffold is provided to occupy the hydrophobic pocket formed by the presence of the special small Gly gatekeeper residue. Among these compounds, compounds 195 and 196 (Figure 52) are the most potent representative TgCDPK1 inhibitors, with IC50 values of 3.4 and 0.69 nM, respectively. Compound 197 is a potent TgCDPK1 inhibitor (IC50 = 1 nM) without hERG inhibitory activity that leads to cardiotoxicity risk in humans.(284) To improve the metabolic stability of the methylene linkage at the C-3 position of compound 197, a heteroatom linkage was introduced to replace it, resulting in compound 198 (IC50 = 10.9 nM), which showed good selectivity and significant efficacy in vivo.(285) Compound 199 (IC50 = 16.5 nM) also displayed good activity, selectivity, safety, and efficacy in vivo.(286)

Figure 52

Figure 52. Chemical structures of TgCDPK1 inhibitors discussed in the text.

As a kinase in the same family, calcium/calmodulin-dependent protein kinase II (CaMKII) mediates the binding/entry of Japanese encephalitis virus, dengue virus and Zika virus of Flaviviridae, which are associated with several severe diseases, such as dengue shock syndrome, Guillain–Barré syndrome, and birth defects.(287) It was reported that compound 200 has potent inhibitory activities against CaMKII, with an IC50 value of 0.79 μM and EC50 values of 1.52 and 1.91 μM toward dengue virus and Zika virus infections in human neuronal BE(2)C cells, respectively.(287) Furthermore, in mouse challenge models, compound 200 markedly lowered the viremia level and increased animal survival time.

3.19. Miscellaneous

In this Perspective, we have already illustrated many kinases for which small-molecule medical agents have been successfully applied (with inhibitors already approved) or have potential (with inhibitors reported) for treatment of nononcologic diseases. In addition, many small-molecule inhibitors of many other kinases present in humans or other species have been reported to have biological activities against different nononcologic disease models. Table 7 summarizes such kinases and their representative inhibitors, most of which were gleaned from articles published in the Journal of Medicinal Chemistry from 2010 to present.
Table 7. Reported Miscellaneous SMKIs with the Potential to Treat Nononcologic Diseases(288−353)
a

No determination

b

The activity of ULK1 activator.

4. Perspectives and Conclusion

ARTICLE SECTIONS
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Because of the similarities among their ATP-binding pockets and the required inhibitory potency to compete with ATP concentrations, which are in the millimolar range in cells, kinases were recognized as difficult targets for drug discovery many years ago when scientists began to try to identify inhibitors to target them. However, great successes have been achieved in targeting kinases, and more than 60 SMKIs have been marketed worldwide in the past two decades. This is an unparalleled achievement in the history of pharmaceutical research, and kinase inhibitor discovery is currently a burgeoning field and is very inspiring. Most of these SMKIs are for cancer treatment. Although it is assumed that oncology will remain the main focus of kinase drug discovery, an increasing number of disclosed SMKIs can treat diseases other than cancer, as we have discussed in this Perspective. There are great opportunities and challenges in developing SMKIs for nononcologic diseases. One focal challenge is that clinical safety for medicines intended for nonlife-threatening indications that require long-term treatment is much more important than for cancer. Therefore, in the nononcologic therapeutic field, SMKIs with sufficient safety profiles are highly desired for application in the clinic.

4.1. Explore New Kinase Targets

The human kinome along includes 518 kinases. Among the kinases in humans, to date, marketed drugs have been successfully produced to target only approximately 40 kinases, leaving more than 90% of the kinome untapped. The majority of kinomes have been understudied, and our understanding of kinase signaling networks and disease pathologies is limited, demonstrating that the field of SMKI discovery is still immature. Therefore, validation of novel kinase targets is necessary for the discovery of more SMKIs for oncology and nononcology therapeutic areas. To this end, it is necessary to explore new kinases to identify their detailed diverse biological processes and functions. A deep understanding of kinase functions and their dysregulation in human disease might result in the identification of more kinase targets to meet unmet medicinal needs.
For the kinases of other species, no small-molecule inhibitors have been approved. By exploring novel kinases in species other than humans, veterinary medications may be developed. Oclacitinib, a JAK inhibitor controlling pruritus and atopic dermatitis in dogs, is one example. More importantly, in the field of infectious disease, by targeting kinases belonging to parasites, viruses, bacteria, or fungi and developing selective and potent small-molecule inhibitors, it should be feasible to obtain next-generation antimicrobial drugs to kill these microorganisms and protect against them. To avoid possible side effects, the selectivity of the developed SMKIs over mammalian orthologues is very important. It should be noted that targeting kinases of other species is still in its infancy.

4.2. Deeply Understand Already Targeted Kinases

Inhibitors of many kinases have already been approved to treat cancer, and inhibitors of many other kinases have demonstrated promising medical potential for cancer treatment in clinical trials or in preclinical studies. A deeper understanding of the biological functions of these kinases may allow inhibitors to be repurposed and applied to nononcologic diseases.
For example, phosphoinositide-dependent protein kinase 1 (PDK1) has attracted much interest for the development of anticancer agents. Biological studies of PDK1 have indicated that this kinase reduces the activity of TACE-mediated α-secretase and accelerates disease progression in AD and prion-related diseases,(354) which indicates that PDK1 may act as a novel target for AD. However, this genetic validation requires proof of concept to ensure the efficacy and safety of PDK1 inhibitors to treat AD.
Another example is anaplastic lymphoma kinase (ALK). ALK inhibitors, such as crizotinib, have been successfully developed for cancer therapy. ALK is mostly expressed in the brain and is therefore related to cognition and neuronal development. Nevertheless, its functions in the CNS are not clear. To elucidate these functions, scientists at Takeda Pharmaceuticals developed a potent selective and brain penetrant ALK inhibitor by employing a scaffold hopping strategy. This ALK inhibitor can decrease the p-ALK level in the brain and may serve as a valuable tool compound to clarify the mechanism underlying ALK-mediated brain functions and the medical applications of ALK inhibition for CNS disorders, such as cognitive impairment, anxiety, and depression.(290)

4.3. Develop Dual or Multitarget Kinase Inhibitors

The severity and heterogeneity of some types of B-cell malignancies and autoimmune diseases make it necessary to simultaneously target two or more signaling pathways that are disease-relevant; therefore, developing SMKIs that target dual (for example, cerdulatinib) or multiple kinases (for example, nintedanib) represents a feasible strategy to elicit several benefits relative to selective SMKIs. These benefits include (1) control over a wider range of disease etiologies, (2) the possibility of selection so that bypass disease mechanisms can be reduced, and (3) lower-level suppression of specific targets can be sufficient to adjust the activities of certain diseases.(355)

4.4. Develop Highly Selective Kinase Inhibitors

Occasionally, dual or multitarget kinase inhibitors are anticipated; nevertheless, in most cases, to develop drug candidates with satisfactory therapeutic indexes, particularly for nonlife-threatening diseases, SMKIs with good isoform and kinome selectivity are of great interest. Such selective kinase inhibitors can also be employed as pharmacological tools to further investigate the biological roles of kinases or related signaling pathways. In kinase inhibitor discovery, obtaining high selectivity is a long-standing problem.(356) Obtaining targeted kinase selectivity to reduce off-target-mediated side effects or toxicity is particularly important for SMKI development in nononcology therapeutic areas. Unlike cancer, most nononcologic diseases, including inflammatory disorders and autoimmune diseases, are not life-threatening and require a long duration of treatment. These types of diseases require much safer treatment options than cancer. At present, the majority of approved SMKIs and SMKIs in preclinical studies are type I or type II kinase inhibitors that occupy the ATP-binding pockets of kinases. The structural and sequence similarities of ATP-binding pockets make selective inhibition of different kinases a formidable task. For type I (ATP-competitive) or type II SMKIs, taking advantage of subtle differences among the binding sites in a kinase family might be a feasible strategy to design and identify selective kinase inhibitors.(260)
To circumvent this, allosteric inhibitors (type III and type IV) targeting sites different from the orthostatic ATP-binding pockets have been discovered. Compared with ATP-competitive inhibitors, due to the structural differences in their allosteric sites, allosteric inhibitors may have higher selectivity among the kinome, improved physiochemical properties, and better side effects or toxicity profiles. In addition, allosteric inhibitors may have the potential to overcome drug resistance, which is related to the administration of ATP-competitive kinase inhibitors.(357,358) For example, TYK2 has a unique catalytically inactive pseudokinase domain, and BMS-986165, a compound targeting this domain, has very high selectivity against TYK2 in the JAK family. GSK2982772, a type III RIPK1 inhibitor, exhibits excellent kinome selectivity, i.e., monokinase selectivity, which may be because this compound is an allosteric inhibitor.
Types I–IV SMKIs can be covalently or noncovalently bound to their targets. Covalent kinase inhibitors have received significant attention due to their potential for high selectivity, sustained target inhibition, better ligand efficiency, improved pharmacodynamics, ameliorated drug resistance, and high systemic drug exposure. Therefore, developing covalent kinase inhibitors is another feasible way to obtain better medications for both cancer and nononcologic diseases if there is a reactive residue in or in close proximity to the active site. To this point, targeting of BTK has shown great success, and most BTK inhibitors on the market or in clinical trials are covalent.

4.5. Proteolysis Targeting Chimera (PROTAC)

Rather than inhibiting a protein, a PROTAC induces selective intracellular proteolysis and then degrades the protein. A PROTAC consists of two protein-binding molecules that are covalently linked with each other: one binds to a target protein for degradation and the other is capable of engaging an E3 ubiquitin ligase. PROTACs provide major advantages over occupancy-based inhibitors and have received much attention for drug discovery. In the field of kinases, PROTACs are still in the early preclinical stages but have demonstrated promise.(359) In the future, more kinases could be explored so that they can be degraded directly by ubiquitylation.
Drug discovery research on kinases has achieved dramatic progress in the past two decades. In the United States, 10 SMKIs have been approved for treatment of several nononcologic diseases. However, each of these drugs has several unwanted side effects. For better medicines to meet unmet significant medical needs, including cancer, inflammatory diseases, CNS disorders, and cardiovascular diseases, among others, the structural diversity, kinase selectivity, and toxicity profiles of SMKIs still need to be improved. With a much deeper understanding of different kinases and accumulated medicinal chemistry knowledge obtained from developing SMKIs, it is anticipated that, in the near future, more SMKIs with better treatment effects will be approved and enter the market for treatment of both cancer and nononcologic diseases.
Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Author Information

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  • Corresponding Author
    • Chenzhong Liao - Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China Email: [email protected] [email protected]
  • Authors
    • Zhouling Xie - Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
    • Xiaoxiao Yang - Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, ChinaOrcidhttp://orcid.org/0000-0003-0290-2844
    • Yajun Duan - Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
    • Jihong Han - Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
  • Author Contributions

    The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

  • Notes

    The authors declare no competing financial interest.

Biographies

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Zhouling Xie

Zhouling Xie received his bachelor’s degree from China Pharmaceutical University, where he also obtained his Ph.D. in Medicinal Chemistry under the supervision of Professor Zhiyu Li. In 2017, he became a member of the Department of Pharmaceutical Sciences and Engineering, Hefei University of Technology in China. He works as a lecturer and medicinal chemist, and his current main research interests focus on the following topics: (i) discovery of selective factor XI inhibitors and (ii) design and study of kinase inhibitors, including PLK inhibitors and CDK inhibitors.

Xiaoxiao Yang

Xiaoxiao Yang received her Ph.D. from Nankai University in 2017 and then worked at Hefei University of Technology as an associate professor. Her research interests include vascular biology, liver diseases, and cancer.

Yajun Duan

Yajun Duan received her Ph.D. from Nankai University in 2009 and then worked at Nankai University as a fellow until 2012 and as an associate professor until 2015. In 2015, she became a full professor at Hefei University of Technology in China. Her research interests include vascular biology, liver diseases, and metabolic syndrome.

Jihong Han

Jihong Han received his Ph.D. from the Medical College of Cornell University in 1995 and then worked at Mount Sinai Medical School as a postdoctoral fellow. From 1996 to 1999, he worked as a research associate and was promoted to an assistant professor in 1999 and an associate professor in 2004 at the Center of Vascular Biology, Weill Medical College of Cornell University. In 2007, he became a full professor at Nankai University. In 2015, he started working at Hefei University of Technology as a professor. His research interests include vascular biology, liver diseases, and cancer.

Chenzhong Liao

Chenzhong Liao received his Ph.D. from the Chinese Academy of Sciences in 2004 and then worked at Shenzhen Chipscreen Biosciences as a drug designer. From 2005 to 2010, he worked as a visiting fellow (postdoc) at the CADD group, Laboratory of Medicinal Chemistry (now Chemical Biology Laboratory), National Cancer Institute at Frederick, National Institutes of Health of the U.S. government. He then took two years working at the Department of Pathology, University of Michigan Medical School. In 2012, he became a full professor at the Department of Pharmaceutical Sciences and Engineering, Hefei University of Technology in China. His research interests include drug design, drug development, cheminformatics, and medicinal chemistry.

Acknowledgments

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This work was financially supported by the National Natural Science Foundation of China (21672050, 81803352) and Fundamental Research Funds for the Central Universities (JZ2020HGTB0052).

Abbreviations Used
AA

alopecia areata

amyloid-β

AD

Alzheimer’s disease

AGC

protein kinase A, G, and C

AKT

protein kinase B

ALS

amyotrophic lateral sclerosis

AML

acute myeloid leukemia

APDS

activated PI3Kδ syndrome

AS

ankylosing spondylitis

ASK1

apoptosis signal-regulating kinase 1

βAR

β-adrenergic receptor

BTK

Bruton’s tyrosine kinase

CaMKII

calcium/calmodulin-dependent protein kinase II

CD

Crohn’s disease

CDK

cyclin-dependent kinase

CLL

chronic lymphocytic leukemia

CLK

cyclin-dependent-like kinase

CNS

central nervous system

COPD

chronic obstructive pulmonary disease

COVID-19

coronavirus disease 2019

CSF1R

colony-stimulating factor 1 receptor

CSU

chronic spontaneous urticaria

DC

dendritic cell

EGFR

epidermal growth factor receptor

FGFR

fibroblast growth factor receptor

FLT3

FMS-like tyrosine kinase 3

GRK

G protein-coupled receptor kinase

GSK3

glycogen synthase kinase 3

GVHD

graft versus host disease

IBD

inflammatory bowel disease

IL

interleukin

IPF

idiopathic pulmonary fibrosis

IRAK4

interleukin-1 receptor-associated kinase

ITK

interleukin-2-inducible T-cell kinase

ITP

immune thrombocytopenia

JAK

Janus kinase

JH2

pseudokinase domain

JNK

c-Jun-N-terminal kinase

KHK

ketohexokinase

KSHV

Kaposi sarcoma-associated herpesvirus

LBCL

large B-cell lymphoma

LPS

lipopolysaccharide

LRRK2

leucine-rich repeat kinase 2

mAb

monoclonal antibody

MAP3K

mitogen-activated protein kinase kinase kinase

MAPK

mitogen-activated protein kinase

MCL

mantle cell lymphoma

MK2

p38/MAPK-activated kinase 2

MS

multiple sclerosis

mTOR

mammalian target of rapamycin

mTORC

mTOR complex

NF-κB

nuclear factor κ light-chain-enhancer of activated B-cells

NGF

nerve growth factor

NHL

non-Hodgkin lymphoma

NIK

NF-κB inducing kinase

NOD

nucleotide oligomerization domain

NSCLC

nonsmall cell lung cancer

p38α MAPK

p38α mitogen-activated protein kinase

PA

psoriatic arthritis

PASLI

p110 δ activating mutation causing senescent T-cells, lymphadenopathy and immunodeficiency

PCV

polycythemia vera

PD

Parkinson’s disease

PDGFR

platelet-derived growth factor receptor

PDK1

phosphoinositide-dependent protein kinase 1

PfCDPK

Plasmodium falciparum calcium-dependent protein kinases

PfCLK3

Plasmodium falciparum cyclin-dependent–like kinase

PfGSK3

Plasmodium falciparum glycogen synthase kinase 3

PfMRK

Plasmodium falciparum MO15-related kinase

PfPI4K

Plasmodium falciparum phosphatidylinositol 4-kinase

PfPKG

Plasmodium falciparum cGMP-dependent protein kinase

PI3K

phosphatidylinositol 3-kinase

PI4K

phosphatidylinositol 4-kinase

PIK

phosphoinositide lipid kinases

PKC

protein kinase C

PLK

polo-like kinase

PP

plaque psoriasis

PROTAC

proteolysis targeting chimera

PTCL

peripheral T-cell lymphoma

RA

rheumatoid arthritis

RIPK

receptor interacting protein kinase

ROCK

Rho-associated protein kinase

SLE

systemic lupus erythematosus

SMKI

small-molecule kinase inhibitor

SS

Sjögren’s syndrome

STAT

signal transducers and activators of transcription

SYK

spleen tyrosine kinase

TgCDPK1

Toxoplasma gondii calcium dependent protein kinase 1

TLR

toll-like receptor

TSC

tuberous sclerosis complex

TRK

tropomyosin receptor kinase

TNF

tumor necrosis factor

TYK2

tyrosine kinase 2

UC

ulcerative colitis

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

WM

Waldenström’s macroglobulinemia

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  • Abstract

    Figure 1

    Figure 1. SMKIs approved by the U.S. FDA. The INNs of drugs (compounds 110) with indications other than cancer are displayed in magenta ellipsoids, and their chemical structures are shown.

    Figure 2

    Figure 2. JAK/STAT signaling pathway. Various cytokines, such as interleukins, interferons, and neurotrophic factors, bind to their corresponding transmembrane receptors, leading to receptor dimerization. Then, JAKs are recruited to the intracellular region of receptors, resulting in the autophosphorylation of JAKs, which subsequently activates their respective STATs. STATs homodimerize/heterodimerize and then translocate into the nucleus to induce the transcription of various downstream targets associated with inflammation and cancer. IL, interleukin; IFN, interferon.

    Figure 3

    Figure 3. (A) Binding mode of tofacitinib to the ATP-binding site of JAK3 (PDB 3LXK). Tofacitinib forms two hydrogen bonds with Glu903 and Leu905. (B) Binding mode of BMS-986165 to TYK2 JH2 (PDB 6NZP). In addition to hydrophobic interactions, five hydrogen bonds between BMS-986165 and the Arg738, Lys642, Glu688, and Val690 residues can be observed.

    Figure 4

    Figure 4. Chemical structures of peficitinib, delgocitinib (approved in Japan), and other JAK inhibitors in clinical trials for nononcologic diseases (compounds 1326).

    Figure 5

    Figure 5. Overview of BTK, SYK, PI3K/AKT/mTOR, MAPK, and related signaling pathways. SRC family kinases, such as Lyn in B/T cells or other cells, phosphorylate ITAM, which then recruits and activates SYK. SYK subsequently phosphorylates several substrates to activate various signaling pathways. SYK activates BTK-PLCγ, which then leads to activation of DAG-PKC and IP3-Ca2+, triggering MAPK signaling, AKT-mediated NF-κB signaling, and calcium mobilization. These pathways are associated with inflammation and cancer. PI3K/AKT/mTOR pathway: CD19, as a coreceptor of B- or T-cell receptors, is activated by Lyn, which then recruits and activates PI3K. PI3K generates PIP3, which recruits BTK and AKT. AKT activation by PDK1 and mTORC2 results in activation of mTORC2 and inhibition of GSK3. These downregulation targets are associated with inflammation, aging, neuropathy, and cancer. MAPK signaling includes the MKK4/7-JNK pathway, MKK3/4/6-p38 pathway, and MEK-ERK pathway. SYK activates the complex SLP65/GRB2/VAV/SOS, leading to activation of the MKK4/7-JNK pathway and MKK3/4/6-p38 pathway, which are associated with inflammation and cancer. PLC, phospholipase; DAG, diacyl glycerol; IP3, inositol triphosphate; IKK, IκB kinase; BCR/TCR, B/T-cell receptor; PIP2, phosphatidyl inositol 4,5-biphosphate; NFAT, nuclear factor of activated T-cells; ITAM, intracellular tyrosine activation; PDK1, 3-phosphoinositide dependent kinase-1; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; GRB2, growth factor receptor-bound protein 2.

    Figure 6

    Figure 6. (A) Irreversible binding mode of evobrutinib to BTK (PDB 6OMU). The covalent bond formed between Cys481 and evobrutinib is highlighted in purple. Evobrutinib forms three hydrogen bonds with the Thr474, Glu475, and Met477 residues. (B) Reversible binding mode of BMS-986142 to BTK (PDB 5T18). BMS-986142 forms two hydrogen bonds with Met477. For comparison, evobrutinib is depicted as a green stick model after superimposition of the X-ray crystal structure of 6OMU onto 5T18.

    Figure 7

    Figure 7. Chemical structures of BTK inhibitors approved (compounds 3, 27, and 28) or in clinical trials (compounds 2937) for indications other than cancer.

    Figure 8

    Figure 8. Selected recently reported BTK inhibitors in preclinical studies.

    Figure 9

    Figure 9. ROCK signaling pathway. As a GTPase, Rho is activated by guanine nucleotide exchange factors (GEFs). Together with GTP, Rho then activates ROCK to phosphorylate various substrates. Among its substrates, ERM, NHE1, adducin, CRMP2, NF-L, MLC, and MARCKS are associated with cellular responses and cytoskeletal regulation. LIMK is involved in the regulation of F-actin stabilization. GEF, guanine nucleotide exchange factors; ERM, ezrin-radixin-moesin; NHE1, sodium hydrogen exchanger 1; CRMP2, myosin light chain phosphatase 2; NF-L, neurofilament protein; MLC, myosin light chain; MLCP, myosin light chain phosphatase; MARCKS, myristylated alanine-rich C-kinase; LIMK, LIM kinases 1 and 2.

    Figure 10

    Figure 10. (A) Chemical structures of ROCK inhibitors approved worldwide. (B) Binding mode of fasudil to ROCK2 (PDB 2F2U). In addition to hydrophobic interactions, three hydrogen bonds and an atypical hydrogen bond (CH···O═C) can be observed between fasudil and the Met172, Asn219, Asp232, and Glu170 residues.

    Figure 11

    Figure 11. Chemical structure of BA-1049 and compound 51 discussed in the text.

    Figure 12

    Figure 12. (A) Structure of tamatinib (52, R-406) and its prodrug fostamatinib (8). (B) Binding mode of tamatinib to SYK (PDB 3FQS). In addition to hydrophobic interactions, two hydrogen bonds, and an atypical hydrogen bond (CH···O═C) can be observed between tamatinib and Ala451 and Glu449.

    Figure 13

    Figure 13. Chemical structures of SYK inhibitors in clinical trials or in trials already being terminated.

    Figure 14

    Figure 14. (A) Chemical structure of sirolimus and its analogues approved for medical uses. (B) Binding mode of sirolimus to mTOR (PDB 4DRH). Sirolimus forms extensive hydrophobic interactions with surrounding residues, and four hydrogen bonds between this drug and the Asp68, Gly84, Ile87, and Tyr113 residues can be observed.

    Figure 15

    Figure 15. Reported mTOR inhibitors demonstrating efficacy in nononcologic disease models.

    Figure 16

    Figure 16. Chemical structures of PI3K inhibitors in clinical trials for nononcologic diseases.

    Figure 17

    Figure 17. (A) Binding mode of nemiralisib to PI3Kδ (PDB 5AE8). In addition to hydrophobic interactions, nemiralisib forms three hydrogen bonds with the Asp787, Glu826, and Val827 residues. (B) Key residues determining the selectivity of nemiralisib among PI3Kα, β, γ, and δ.

    Figure 18

    Figure 18. Chemical structures of recently reported PI3K inhibitors demonstrating interesting biological effects in nononcologic disease models.

    Figure 19

    Figure 19. (A) Chemical structure of omipalisib (GSK2126458). (B) Binding mode of omipalisib to PI3Kγ (PDB 3L08). Two hydrogen bonds are formed between omipalisib and the Ser806 and Val882 residues. In addition, a bridged hydrogen bond and one atypical CH···O═C hydrogen bond can be observed.

    Figure 20

    Figure 20. FLT3 signaling pathway. FLT3 recruits PI3K via the adaptor protein GRB2 or by forming multiprotein complexes. Subsequently, PI3K activates the MAPK pathway and PI3K/AKT/mTOR pathway, as shown in Figure 5.

    Figure 21

    Figure 21. Chemical structures of a few FLT3 inhibitors discussed in the text.

    Figure 22

    Figure 22. Role of ASK1 in the MKK4/7-JNK and MKK3/4/6-p38 signaling pathways. ASK1 is activated by inflammatory cytokine signaling and oxidative stress, which then leads to activation of MKK4/7 and MKK3/4/6, triggering the JNK and p38 signaling pathways. RTKs, receptor tyrosine kinases; TRADD, tumor necrosis factor receptor-associated death protein; Daxx, death domain-associated protein; TRAF2, TNF receptor-associated factor 2.

    Figure 23

    Figure 23. Chemical structures of reported ASK1 inhibitors discussed in the text.

    Figure 24

    Figure 24. Binding mode of selonsertib to ASK1 (PDB 6OYT). Selonsertib forms two hydrogen bonds with Lys709 and Val757. In addition, it has extensive hydrophobic interactions with surrounding residues, including Leu686, Val694, Ala707, Met754, Val757, and Leu810.

    Figure 25

    Figure 25. Chemical structures of four reported selective RIPK1 inhibitors.

    Figure 26

    Figure 26. Binding mode of GSK2982772 to RIPK1 (PDB 5TX5). One hydrogen bond and a bridged hydrogen bond can be observed between GSK2982772 and the Asp156 and Val76 residues. GSK2982772 has extensive hydrophobic interactions with Val31, Ile43, Lys45, Met67, Leu70, Val75, Val76, Leu78, Leu90, Met92, Leu129, Val134, and Phe162.

    Figure 27

    Figure 27. Chemical structures of six reported selective RIPK2 inhibitors.

    Figure 28

    Figure 28. Binding mode of compound 100 to RIPK2 (PDB 6RNA). Three hydrogen bonds can be observed between 100 and Ser25, Met98, and Asp164. An atypical CH···O═C hydrogen bond can be found between 100 and Met98. Additionally, 100 has extensive hydrophobic interactions with Leu24, Ala45, Lys47, Leu70, Leu79, Ile93, Tyr97, Met98, Leu153, and Ala163.

    Figure 29

    Figure 29. Role of IRAK4 in the MKK3/4/6-p38 and MKK4/7-JNK signaling pathways. Once ligands such as LPS and IL-1 bind to the IL-1 receptor (IL-1R) and Toll-like receptors (TLRs), respectively, IRAK4 is recruited and activated by the adaptor protein MyD88. IRAK4 then activates IRAK1-TRAF6, stimulating the NF-κB, JNK and p38 pathways. In addition, IRAK1 activates IRAK2 to regulate the expression of caspase-8. FADD, Fas-associating protein with a novel death domain; Casp-8, caspase-8.

    Figure 30

    Figure 30. Chemical structures of IRAK4 inhibitors in clinical trials (A) and recently reported (B).

    Figure 31

    Figure 31. Binding mode of PF-06650833 to IRAK4 (PDB 5UIU). PF-06650833 forms three hydrogen bonds with Val263, Met265, and Ser328 and two bridged hydrogen bonds with Lys213 and Ser269.

    Figure 32

    Figure 32. GSK3 signaling pathway. GSK3 can be activated by PI3K signaling, regulating protein synthesis and glycogen synthesis. Binding of WNT to Frizzled and LRP5/6 complex results in recruitment and activation of Dsh protein, which then inhibits a protein complex containing GSK3, AXIN, APC, CKII, and β-catenin, blocking the phosphorylation and consequent degradation of β-catenin. Once D2 receptor activation occurs, β-arrestin brings AKT and GSK3 to PP2A. PP2A dephosphorylates AKT and GSK3, deactivating AKT and activating GSK3. LRP5/6, LDL receptor-related protein 5/6; PP2A, protein phosphatase 2A.

    Figure 33

    Figure 33. Chemical structures of GSK3 inhibitors in clinical trials.

    Figure 34

    Figure 34. Chemical structures of several recently reported GSK3 inhibitors.

    Figure 35

    Figure 35. Binding mode of BRD3937 to human GSK3β (PDB 5HLP). BRD3937 forms three hydrogen bonds with residues Asp133 and Val135.

    Figure 36

    Figure 36. (A) Chemical structures of BMS-751324 and MW150. (B) Binding mode of MW150 to human p38α MAPK (PDB 4R3C). MW150 forms hydrophobic interactions with surrounding residues; three hydrogen bonds between MW150 and the Lys53, Met109, and Ser154 residues can be observed.

    Figure 37

    Figure 37. (A) The deep and narrow ATP-binding site of MK2 (PDB 1NY3). An ADP (green ball and stick mode) is shown. (B) Binding mode of an analogue of compound 144 to MK2 (PDB 3FYJ). Two hydrogen bonds can be observed between this compound and Lys93 and Leu141. An atypical CH···O═C hydrogen bond can be found between this compound and Glu139. Additionally, this compound has extensive hydrophobic interactions with Leu70, Val78, Ala91, Lys93, Val118, Met138, Leu141, and Leu193.

    Figure 38

    Figure 38. Chemical structures of MK2 inhibitors discussed in the text.

    Figure 39

    Figure 39. TRK signaling pathway. Neurotrophins bind to TRK receptors, leading to recruitment of adaptor proteins, including GRB2, GAB1, SHC, SHP2, FRS2, and SOS. Subsequently, Ras, PLC-γ, and PI3K are activated, triggering the MAPK pathway, calcium mobilization, and the PI3K/AKT/mTOR pathway. These signaling pathways regulate gene expression activation, neurite outgrowth, and neuronal survival associated with pain and cancer.

    Figure 40

    Figure 40. Chemical structures of several reported TRK inhibitors.

    Figure 41

    Figure 41. (A) Binding mode of PF-06273340 (PDB 5JFX) to TRK-A. PF-06273340 forms three hydrogen bonds with the Met592 and Asp668 residues and two bridged hydrogen bonds with the Arg574 and Glu590 residues. (B) Binding mode of compound 152 (PDB 6D20) in an allosteric pocket of TRK-A. Compound 152 forms four hydrogen bonds with Leu486, Asp668, and Arg673. An NH+–π interaction can be observed. For comparison, PF-06273340 is shown as a green wire model.

    Figure 42

    Figure 42. Chemical structures of representative JNK inhibitors for treatment of nononcologic diseases.

    Figure 43

    Figure 43. Chemical structures of representative selective LRRK2 inhibitors.

    Figure 44

    Figure 44. Chemical structures of three reported KHK inhibitors.

    Figure 45

    Figure 45. Binding mode of PF-06835919 to KHK (PDB 6W0Z). Three hydrogen bonds with Arg108, Ala256, and Gly257 and a bridged hydrogen bond with Cys282 can be observed between PF-06835919 and KHK.

    Figure 46

    Figure 46. GRK2 signaling pathway. In the adrenal medulla and cardiac sympathetic nerve terminal, upregulation of GRK2 leads to α2 adrenergic receptor (α2AR) dysfunction, causing a massive release of catecholamines (norepinephrine and epinephrine). Catecholamines in turn stimulate the βARs present on cardiomyocytes, activating AKT and GRK2. GRK2 blocks sphingosine 1-phosphate (S1P) receptor 1 (S1PR1) signaling, which is involved in regulation of the contractile response and cardiac hypertrophy. In addition, GRK2 phosphorylates insulin receptor substrate-1 (IRS1), blocking glucose transporter type 4 (GLUT4) translocation from the cytosol to the plasma membrane. GRK2 also regulates β-oxidation rates and increases activation of the mitochondrial permeability transition pore (MPTP), which is associated with cellular death.

    Figure 47

    Figure 47. Chemical structures of representative GRK2 inhibitors discussed in the text.

    Figure 48

    Figure 48. Chemical structures of six NIK inhibitors discussed in the text.

    Figure 49

    Figure 49. Binding mode of compound 177 to murine NIK (PEB 6G4Z). Compound 177 forms hydrophobic interactions with surrounding residues, and four hydrogen bonds between this compound and residues Glu442, Glu472, Leu474, and Asp536 can be observed.

    Figure 50

    Figure 50. Chemical structures of a few reported selective PLK2 inhibitors.

    Figure 51

    Figure 51. Chemical structures of inhibitors of plasmodial kinases discussed in the text.

    Figure 52

    Figure 52. Chemical structures of TgCDPK1 inhibitors discussed in the text.

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